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    policy of the United Nations Environment Programme, the International
    Labour Organisation, or the World Health Organization.

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

    World Health Orgnization
    Geneva, 1990

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    WHO Library Cataloguing in Publication Data

    Fully halogenated chlorofluorocarbons.

        (Environmental health criteria ; 113)

        1.Freons - adverse effects 2.Freons - toxicity 

        ISBN 92 4 157113 6 0        (NLM Classification: QV 633)
        ISSN 0250-863X

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 1. SUMMARY                

     1.1. Identity, physical and chemical properties, analytical methods   
     1.2. Sources of human and environmental exposure  
     1.3. Environmental transport, distribution, and transformation    
     1.4. Environmental levels and human exposure  
     1.5. Kinetics and metabolism  
     1.6. Effects on the environment   
     1.7. Effects on experimental animals and in vitro systems     
     1.8. Effects on humans    
     1.9. Evaluation of human health risks 


     2.1. Identity     
           2.1.1. Technical product   
     2.2. Physical and chemical properties 
     2.3. Conversion factors   
     2.4. Analytical methods   


     3.1. Natural occurrence   
     3.2. Man-made sources 
           3.2.1. Production levels   
           3.2.2. Manufacturing processes 
           3.2.3. Loss during disposal of wastes  
           3.2.4. Release from transport, storage, and accidents  
           Transport and storage   
     3.3. Use patterns     
           3.3.1. Major uses  
           3.3.2. Release from use: controlled or uncontrolled    


     4.1. Transport between media  
     4.2. Environmental transformation and degradation processes       
           4.2.1. Oxidation   
           4.2.2. Hydrolysis  
           4.2.3. Photolysis  
           Environmental transformation    
           4.2.4. Biodegradation  
     4.3. Interaction with other physical, chemical, or biological factors
     4.4. Bioconcentration and bioaccumulation 


     5.1. Environmental levels 
           5.1.1. Air     

           5.1.2. Water       
           5.1.3. Food and other edible products  
     5.2. Occupational exposure    


     6.1. Introduction     
     6.2. Terrestrial plants   
     6.3. Aquatic organisms    
     6.4. Research needs       


     7.1. Absorption       
     7.2. Distribution     
     7.3. Metabolic transformation 
     7.4. Elimination and excretion in expired air, faeces, and urine  
     7.5. Retention and turnover   
     7.6. Reaction with body components    


     8.1. Single exposures 
           8.1.1. Acute inhalation toxicity   
           8.1.2. Acute oral toxicity 
     8.2. Short-term exposures 
           8.2.1. Inhalation exposure 
           8.2.2. Oral toxicity   
           8.2.3. Dermal toxicity 
     8.3. Skin and eye irritation; sensitization   
     8.4. Long-term exposures  
           8.4.1. Inhalation toxicity 
           8.4.2. Oral toxicity   
     8.5. Reproduction and developmental toxicity  
           8.5.1. Reproduction    
           8.5.2. Developmental toxicity  
     8.6. Mutagenicity and related end-points  
     8.7. Carcinogenicity      
     8.8. Special studies - cardiopulmonary effects    
           8.8.1. Cardiac sensitization in response to exogenous 
                    adrenaline-induced arrhythmia 
           8.8.2. Cardiac sensitization and asphyxia-induced arrhythmia   
           8.8.3. Arrhythmia not associated with asphyxia or adrenaline
     8.9. Mechanisms of toxicity - mode of action  


     9.1. Controlled studies with volunteers   
     9.2. Occupational exposure    
     9.3. Non-occupational exposures   
     9.4. Health effects associated with stratospheric ozone depletion
           9.4.1. Skin cancer effects 
           9.4.2. Immunotoxic effects 
           9.4.3. Ocular effects  

           9.4.4. Effects on vitamin D synthesis  
           9.4.5. Exacerbation of photochemical smog formation and 


     10.1. Evaluation of human health risks 
           10.1.1. Direct health effects resulting from exposure to fully
                    halogenated chlorofluorocarbons 
           10.1.2. Health effects expected from reduction of stratospheric 
                    ozone by chlorofluorocarbons   
     10.2. Effects on the environment   
     10.3. Conclusions      







MEDIO AMBIENTE               




Dr B. Gilbert, Company for the Development of Technology
   Transfer, Cidade Universitaria, Campinas, Brazil

Professor H.A. Greim, Institute of Toxicology and Biochem-
   istry, Association for Radiation and Environmental
   Research, Neuherberg, Federal Republic of Germany

Dr L. Hinkova, Toxicologist, Institute of Hygiene and
   Occupational Health, Sofia, Bulgaria

Dr Y. Lessard, Laboratory of Medical Physiology, Faculty
   of Medicine, University of Rennes, France

Dr M. Morita, Department of Legal Medicine, Sapporo Medi-
   cal College, Sapporo, Japan

Dr G. Neumeier, Federal Office for the Environment,
   Berlin, Federal Republic of Germany

Professor M. Noweir, Occupational Health Research Centre,
   Higher Institute of Public Health, University of
   Alexandria, Alexandria, Egypt

Dr J. Sokal, Department of Toxicity Evaluation, Institute
   of Occupational Medicine, Lodz, Poland

Professor J.C. Van der Leun, Institute of Dermatology,
   State University Hospital of Utrecht, Utrecht,

Dr K. Victorin, National Institute of Environmental Medi-
   cine, Department of Environmental Hygiene, Stockholm,

Dr W.D. Wagner, National Institute of Occupational Safety
   and Health, Cincinnati, Ohio, USA

Dr R.C. Worrest, Stratospheric Ozone Research Program,
   Office of Environmental Processes and Effects Research,
   US Environmental Protection Agency, Washington, D.C.,


Dr D. Mayer, Toxicology Department, Hoechst AG, Frankfurt
   am Main, Federal Republic of Germany

Dr H. Trochimowicz, E.I. Du Pont de Nemours, Haskell Lab-
   oratory for Toxicology and Industrial Medicine, Newark,
   Delaware, USA

 Representatives of Host Country

Dr U. Schlottmann, Federal Ministry for the Environment,
   Nature Conservation and Nuclear Safety, Bonn, Federal
   Republic of Germanyb

Dr V. Quarg, Federal Ministry for the Environment, Nature
   Conservation and Nuclear Safety, Bonn, Federal Republic
   of Germanyb


Professor F. Valic, IPCS Consultant, World Health Organiz-
   ation, Geneva, Switzerland (Responsible Officer and

Dr S. Lutkenhoff, Office of Health and Environmental
   Assessment, US Environmental Protection Agency,
   Cincinnati, Ohio, USA

Dr G. Quélennec, Division of Vector Biology and Control,
   World Health Organization, Geneva, Switzerland

a  Vice-rector, University of Zagreb, Zagreb, Yugoslavia.
b  Present for part of the meeting only.


    Every effort has been made to present information in
the criteria monographs as accurately as possible without
unduly delaying their publication.  In the interest of all
users of the environmental health criteria monographs,
readers are 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 or 7985850).


    A WHO Task Group on Environmental Health Criteria for
Fully Halogenated Chlorofluorocarbons met at the Institute
of Toxicology and Biochemistry, Neuherberg, Federal Repub-
lic of Germany, from 21 to 25 November 1988.  Professor
H.A. Greim opened the meeting on behalf of the host insti-
tute.  Dr U. Schlottmann spoke on behalf of the Federal
Government, which sponsored the meeting.  Professor
F. Valic welcomed the members on behalf of the three
cooperating organizations of the IPCS (UNEP/ILO/WHO).  The
Task Group reviewed and revised the draft criteria mono-
graph and made an evaluation of the risks for human health
and the environment from exposure to fully halogenated

        The drafts of this monograph were prepared by the
Office of Health and Environmental Assessment, US Environ-
mental Protection Agency, under the direction of Dr J.
STARA and Dr S. LUTKENHOFF. The chapter on the ecological
effects of stratospheric ozone depletion was prepared by
Dr R.C. WORREST and the section on the health effects
associated with stratospheric ozone depletion by Dr L.
GRANT, both of the US Environmental Protection Agency.
Professor F. Valic and Dr P.G. Jenkins (IPCS) were respon-
sible for the overall scientific content and editing,


ADI        Acceptable daily intake

ADP        Adenosine diphosphate

bw         Body weight

CFC        Chlorofluorocarbon

EC         Electron capture

ECG        Electrocardiogram

EEG        Electroencephalogram

FEV        Forced expiratory volume

FI         Flame ionization

GC         Gas chromatography

HCFH-22    Chlorodifluoromethane (CHClF2)

LDH        Lactate dehydrogenase

LOEL       Lowest-observed-effect level

MS         Mass spectrometry

NMR        Nuclear magnetic resonance

NOEL       No-observed-effect level

ppb        Parts per billion

ppm        Parts per million

ppt        Parts per trillion

SGOT       Serum glutamic oxaloacetic transaminase

SGPT       Serum glutamic pyruvic transaminase

TWA        Time-weighted average

UV         Ultraviolet

v/v        Volume per volume

w/v        Weight per volume


1.1.  Identity, physical and chemical properties, analytical methods

    This monograph concerns only those chlorofluorocarbons
(CFCs)  that are derived from the complete substitution of
the  hydrogen atoms in methane and ethane with both fluor-
ine  and chlorine atoms.  Many  of these compounds are  of
commercial significance and some of them are known to con-
tribute  to ozone depletion.  Compounds considered in this
report include: trichlorofluoromethane (CFC-11), dichloro-
difluoromethane (CFC-12), chlorotrifluoromethane (CFC-13),
1,2-difluoro-1,1,2,2-tetrachloroethane (CFC-112), 1,1-difluoro-
1,2,2,2-tetrachloroethane (CFC-112a), 1,1,2-trichloro-1,2,2-
trifluoroethane (CFC-113), 1,1,1-trichloro-2,2,2-trifluoroeth-
ane (CFC-113a), 1,2-dichloro-1,1,2,2-tetrafluoroethane (CFC-
114), 1,1-dichloro-1,2,2,2-tetrafluoroethane  (CFC-114a), and
1-chloro-1,1,2,2,2-pentafluoroethane  (CFC-115). Compounds
not  containing chlorine have  not been considered.  Those
compounds containing hydrogen will be reviewed in  a  sub-
sequent report.

    Commercial  chlorofluorocarbons rank among the highest
purity  organic  chemicals  available.  They  are  usually
characterized  by high vapour pressure and density and low
viscosity,  surface  tension, refractive  index, and solu-
bility  in  water.   The degree  of  fluorine substitution
greatly  affects the physical properties  and, in general,
as  fluorine  substitution increases,  the vapour pressure
increases,  and the boiling point, density, and solubility
in water decrease.

    The chlorofluorocarbons reviewed in this monograph are
reasonably  stable chemically and, in the absence of metal
catalysts,  exhibit  low  rates of  hydrolysis.   They are
highly  resistant  to  attack  by  conventional  oxidizing
agents  at temperatures below 200 °C.  In general, chloro-
fluorocarbons  show a high degree of thermal stability and
are  extremely resistant to almost  all chemical reagents.
However,  they  will  interact violently  with  chemically
reactive metals.

    Several  analytical methods are available  for the de-
termination of chlorofluorocarbons in various media. These
include spectrophotometry, gas chromatography with several
quantification   methods,  and  mass   spectrometry.   The
majority   of  methods  utilize  gas  chromatography  with
various  detection  techniques,  and detection  limits are
often  of the order of 1 part per trillion (ppt).  Methods
for  sample  collection  have  been  modified  to  achieve
greater selectivity and sensitivity.

1.2.  Sources of human and environmental exposure

    The  chlorofluorocarbons  discussed in  this monograph
are not known to occur naturally in the  environment,  but
practically  all chlorofluorocarbons, except those used as
chemical intermediates, are released into the environment.
The  estimated  world  production of  the important poten-
tially  ozone-depleting chlorofluorocarbons (CFC-11,  CFC-
12,  CFC-113) in 1985 was at least a million tonnes. Manu-
facture  is not limited  to major industrial  nations;  it
occurs  in at least 16 countries.  With the implementation
of  the Montreal Protocol, the present growth trend in the
production  of these chlorofluorocarbons will  probably be

    The  most important method for manufacturing the major
chlorofluorocarbons  is  the  catalytic  displacement   of
chlorine from chlorocarbons with fluorine by reaction with
anhydrous  hydrogen fluoride. Most release to the environ-
ment  occurs  during  the disposal  of  waste refrigerant-
containing equipment, and not during manufacture, storage,
or handling. The release of propellant chlorofluorocarbons
has decreased as a result of legislative  restrictions  on
their  use in many countries,  and the release of  blowing
agents is small.  Because of the high vapour  pressure  of
these compounds at ambient temperatures, almost all of the
amount  released  into the  environment eventually accumu-
lates  in  the  atmosphere.  The  estimated  total  annual
release  of  about one  million  tonnes consisted  in 1985
largely of CFC-11 and CFC-12, and the  cumulative  release
of these chlorofluorocarbons from 1931 to 1985  was  about
13.5 million tonnes.

    The  approximate world use pattern of chlorofluorocar-
bons  in  1985 was  as  follows: refrigerants,  15%; foam-
blowing  agents,  35%;  aerosol propellants,  31%; miscel-
laneous, 7%, and unallocated, 12%. In the USA, the aerosol
propellant use was much lower because of restrictions.

1.3.  Environmental transport, distribution, and transformation

    The  commercial chlorofluorocarbons are  persistent in
the  environment because of their chemical stability.  The
average residence times in the atmosphere are estimated to
be 65, 110, 400, 90, 180, and 380 years for  CFC-11,  CFC-
12,  CFC-13, CFC-113, CFC-114, and  CFC-115, respectively.
These  long residence times will ensure diffusion into the
stratosphere  where, via photochemically-produced chlorine
atoms,  the chlorofluorocarbons will react  with the ozone
layer.   Additionally, these compounds will  contribute to
the greenhouse effect.

1.4.  Environmental levels and human exposure

    The  global  distribution  of chlorofluorocarbons  has
been  reported by several investigators.   Recent measure-
ments of latitudinal variations of chlorofluorocarbon con-
centrations  indicate little difference in CFC-11 and CFC-
12  concentrations between the northern and southern hemi-
spheres. Also there is no significant variation with alti-
tude up to 6 km above the Earth's surface.   The  measured
concentrations  of  chlorofluorocarbons in  urban/suburban
air are higher than those in rural/remote areas because of
contributions from local sources of emission.

    Atmospheric  levels  of  CFC-11 and  CFC-12  increased
steadily  up to 1985, when  combined levels for these  two
compounds  in  the USA  were 9120 ng/m3 in  urban/suburban
areas  and 2720 ng/m3 in  rural/remote areas for both com-
pounds.  From these data, human inhalation intake has been
estimated  at 182  and 54 mg/day  in these  two  types  of

    The  mean surface ocean  concentrations of CFC-11  and
CFC-12,  reported  from three  mutually distant locations,
were of the order of 0.2 ng/litre. However, 0.62 ng CFC-11
per  litre was measured in  the Greenland Sea in  1982 and
values  of  up  to  0.54 ng/litre  have  been  measured in
Japanese  coastal  waters.   The highest  value for CFC-12
reported  was 0.33 ng/litre in these  same coastal waters.
Much  higher levels have been  measured in fresh water  in
Lake Ontario where 249 mg CFC-11 per litre and 572 ng CFC-
12 per litre have been recorded.  Chlorofluorocarbons have
not been detected in drinking-water, but have  been  found
in  snow and rain water in Alaska, in Lake Ontario, and in
the Niagara river. CFC-11 has been detected at  levels  of
0.1-5 µg/kg  (ppb) (dry weight basis) in various organs of
fish  and molluscs. However, the presence of chlorofluoro-
carbons in processed food has not been documented.

1.5.  Kinetics and metabolism

    Chlorofluorocarbons  may  enter the  human organism by
inhalation,  ingestion, or dermal contact.   Inhalation is
the  most common and important  route of entry, and  exha-
lation is the most significant route of  elimination  from
the  body. Controlled studies with  volunteer subjects and
experimental  animals have provided substantial  data from
exposures  to a number of  the chlorofluorocarbons.  These
data indicate that chlorofluorocarbons:

*   can  be absorbed across the alveolar membrane, gastro-
    intestinal tract, or the skin;
*   are  absorbed rapidly into the  blood, following inha-
*   are  absorbed into the blood  at a decreasing rate  as
    blood concentration increases;

*   once in the blood, are absorbed by various tissues;
*   will  reach a stable blood  level if exposure is  suf-
    ficiently  long, indicating an equilibrium between the
    air   containing   the  chlorofluorocarbons   and  the
*   are still absorbed by body tissue, after  the  initial
    blood  level stabilization, and continue  to enter the

    Studies with animals indicate that chlorofluorocarbons
are  rapidly absorbed after inhalation and are distributed
by  blood into practically  all tissues of  the body.  The
highest  concentrations  are  usually found  in  fatty  or
lipid-containing tissues. However, chlorofluorocarbons are
also  found in  organs with  a good  blood  supply,  e.g.,
heart, lung, kidney, muscle.

    Results  from animal and human  metabolic studies have
demonstrated  the  resistance  of  chlorofluorocarbons  to
breakdown  or metabolic transformation in  biological sys-
tems.  These results suggest that  chlorofluorocarbons, in
general,  are metabolized to  a very small  degree, if  at
all, following exposure.

    Regardless  of the route of entry, chlorofluorocarbons
are  eliminated almost exclusively through the respiratory
tract  via exhaled air. No significant recovery of chloro-
fluorocarbons  or their metabolites  has been reported  in
studies  attempting  to identify  metabolic transformation
products via elimination in urine or faeces.

1.6.  Effects on the environment

    Certain  chlorofluorocarbons,  including  CFC-11,  12,
113, 114, and 115, are extremely stable  under  conditions
found  in the  lower atmosphere.   It is  not until  these
gases  migrate into the high-energy  radiation environment
of  the upper stratosphere that photolytic processes split
the  chlorine  off  from the  chlorofluorocarbons.   These
chlorine  radicals  catalytically destroy  ozone.  Strato-
spheric  ozone absorbs solar ultra-violet radiation (UV-B:
280-320 nm  wavelength)  allowing only  reduced UV-B radi-
ation to penetrate to the surface of the earth.

    Experimental  evidence  suggests  that increased  UV-B
irradiation  at the Earth's surface,  resulting from ozone
depletion,  would have deleterious effects on both terres-
trial  and aquatic biota.  Despite uncertainties resulting
from  the complexities of field experiments, the data cur-
rently  available suggest that crop yields and forest pro-
ductivity are vulnerable to increased levels of solar UV-B
radiation.  Existing data also suggest that increased UV-B
radiation  will modify the  distribution and abundance  of
plants, and change ecosystem structure.

    Various studies of marine ecosystems have demonstrated
that  UV-B radiation causes damage to fish larvae and juv-
eniles,  shrimp larvae, crab larvae,  copepods, and plants
essential  to the marine food web.  These damaging effects
include  decreased fecundity, growth, and survival. Exper-
imental  evidence  suggests  that even  small increases in
ambient  UV-B exposure could result in significant ecosys-
tem changes.

1.7.  Effects on experimental animals and  in vitro systems

    The  acute inhalation toxicity  of chlorofluorocarbons
has been extensively studied. The chlorofluorocarbons con-
sidered in this monograph show low acute  inhalation  tox-
icity.  The symptomatology of acute  intoxication involves
CNS  effects, secondary effects on the cardiovascular sys-
tem, and irritation of the respiratory tract.  The limited
information  available  on  the  acute  oral  toxicity  of
chlorofluorocarbons  indicates low toxicity.  When applied
dermally  in  high  doses, CFC-112,  CFC-112a, and CFC-113
cause  various degrees of irritation but no other signifi-
cant effects.

    Short-term  inhalation studies have been  reported for
CFC-11,  CFC-12,  CFC-112, CFC-113,  CFC-114, and CFC-115.
The  results showed low toxicity, and the effects observed
were related mainly to the CNS, respiratory tract, and the
liver. Oral toxicity studies have confirmed the  low  tox-

    In  a long-term inhalation study, rats were exposed to
CFC-113 at 0.2, 1, or 2% (15.3, 76.6, or  183 g/m3)    6 h
per day, 5 days/week for up to 2 years. No histopathologi-
cal  effects or changes in clinical laboratory values were
observed.  The only finding considered by the  authors  to
be treatment-related was a reduction in body  weight  gain
in the groups exposed to the two highest doses.

    The  available  information  indicates that  the fully
halogenated  chlorofluorocarbons  evaluated in  this mono-
graph have little or no mutagenic or  carcinogenic  poten-
tial.  Negative results have been obtained in vitro  using
bacteria  and  mammalian  cells with  or without metabolic
activation and in the dominant lethal test.

    Long-term  carcinogenicity studies (by oral  and inha-
lation  routes) with CFC-11  and CFC-12 in  rats and  mice
showed  negative results.  Although a tumorogenic response
in the nasal cavity was observed in rats  upon  inhalation
of  CFC-113, this response was  considered equivocal.  The
tumours  were of various  morphologies and the  incidences
were not dose-related.

    Of  the  eight  chlorofluorocarbons reviewed  in  this
document,   developmental   toxicity  studies   have  been
reported  in the available scientific  literature for CFC-
11,  CFC-12, and CFC-113.  No  evidence of embryotoxicity,
fetotoxicity,  or  teratogenicity has  been documented for
any of these three chlorofluorocarbons.

1.8.  Effects on humans

    Controlled  studies  of  volunteers using  CFC-11  and
CFC-12 revealed  no observable effects on  clinical haema-
tology and chemistry, EEG, or neurological parameters.

    At   high   concentrations,  subjects   experienced  a
tingling sensation, humming in the ears, and apprehension.
EEG changes were noted as well as slurred speech  and  de-
creased performance in psychological tests. An exposure to
an  11%a (545 g/m3)    concentration of CFC-12  for 11 min
caused a significant degree of cardiac arrythmia, followed
by a decrease in consciousness with amnesia after 10 min.
    Following  exposure to CFC-12 at a concentration of 1%
(50 g/m3)   for 150 min, a 7% decrease in psychomotor test
scores  was noted, but  no effects were  observed at  0.1%
(5 g/m3).

    In a study in which 10 subjects were exposed  to  CFC-
11,  CFC-12, CFC-114, two  mixtures of CFC-11  and CFC-12,
and  a mixture of  CFC-12 and CFC-114  (breathing  concen-
trations between 16 and 150 g/m3)   for 15, 45, or 60 sec-
onds,  significant  acute  reduction of  ventilatory  lung
capacity (FEF50, FEF25) was reported in each case, as well
as bradycardia and increased variability in heart rate and
atrioventricular block.

    Psychomotor performance was evaluated using CFC-113 at
concentrations  of  0.15%  (12 g/m3),    0.25%    (19 g/m3),
0.35% (27 g/m3),   or 0.45% (35 g/m3)   for 165 min. There
was no effect at the lowest concentration, but  there  was
difficulty  in mental concentration  and some decrease  in
test scores beginning at 0.35% (27 g/m3).

a   Throughout this monograph, percentages of chlorofluorocarbons
    in air are expressed as the volume of chlorofluorocarbon divided 
    by the volume of air. 

    Limited studies indicate that individuals with a prior
history  of skin reaction  to deodorant sprays  containing
CFC-11  or CFC-12 may  become sensitized to  dermal appli-
cations  of  certain  chlorofluorocarbons.   The  tracheal
mucociliary  function in five non-smokers was not impaired
by exposure to CFC-11.

    Two  studies suggest that normal occupational exposure
to  CFC-113 does  not pose  a serious  health hazard.   No
adverse effects occurred at occupational levels as high as
0.47%  (36.7 g/m3),    with  an  average  level  of  0.07%
(5.4 g/m3).

    Although  chlorofluorocarbons have been used  for over
50 years,  only one cohort study  (539 exposed workers) is
available.  No increase in  total deaths or  tumour deaths
was observed.

    Significant  acute  reduction in  the ventilatory lung
capacity of hairdressers using chlorofluorocarbon-contain-
ing  hairsprays was observed in several studies.  Cases of
neurological  effects attributed to  occupational exposure
to  chlorofluorocarbons have been  reported.  One case  of
neuropathy  in a laundry  worker, exposed to  tetrachloro-
ethene  and to undetermined levels of CFC-113 for 6 years,
has been described.

    Non-occupational  exposure  and accidental  or abusive
inhalation of aerosols have also been documented, the main
symptoms  being  CNS  depression and  cardiovascular reac-
tions.  Cardiac arrythmia, possibly aggravated by elevated
levels  of  catecholamines due  to  stress or  by moderate
hypercapnia,  is suggested as  the cause of  these adverse
responses, which may lead to death.

    Increased UV-B radiation is expected to lead  to  pre-
dominantly  adverse effects on human health, but the state
of  knowledge varies greatly  from one effect  to another.
It  is  virtually undisputed  that  the incidence  of non-
melanoma skin cancers will increase.  Projections based on
recent  data indicate that  the incidence of  non-melanoma
skin cancers will increase by 3% for every 1% depletion of
ozone. On this basis, an ozone depletion by 5% would lead,
after  several  decades,  to about  240 000 additional new
cases of non-melanoma skin cancer per year, worldwide.

    UV-B radiation appears also to play a role in the for-
mation of the more dangerous cutaneous melanomas. However,
there  is  insufficient  knowledge to  determine  accurate
dose-response relationships.

    The immune system is influenced by UV-B  radiation  in
various  ways. Although the knowledge  available is insuf-
ficient to predict the consequences of ozone depletion for

human  health, increased incidence of some infectious dis-
eases might be one of the consequences.

    The most important effect for the human eye  would  be
an  increase in the  incidence of cataracts,  a  permanent
clouding  of the  eye lens  which leads,  even at  current
levels of UV-B radiation, to impaired vision and blindness
in many people.

    Increased UV-B radiation would be expected to increase
photochemical  smog, and this would  aggravate the related
health problems in urban and industrialized areas.

1.9.  Evaluation of human health risks

    The most important direct effects on humans  from  ex-
posure  to chlorofluorocarbons are caused by the excessive
concentrations resulting from industrial accidents or poor
occupational  practices and from  misuse or abuse  of  the
chemicals  when used as  solvents or as  propellant gases.
Release of chlorofluorocarbons into the global environment
during use, disposal of wastes, transport, and storage are
an increasing concern because of the potential impact such
uncontrolled  releases may have  on the future  health  of
mankind,  mainly  through  the depletion  of stratospheric


2.1.  Identity

    The  chlorofluorocarbons  (CFCs)  considered  in  this
monograph  are compounds derived  by the complete  substi-
tution  of the hydrogen atoms  in methane and ethane  with
both fluorine and chlorine atoms. Chlorofluorocarbons con-
taining hydrogen (designated HCFC) will be reviewed  in  a
subsequent report. The chemical formulae, relative molecu-
lar  masses, common names, common synonyms, and CAS Regis-
try  numbers of some  of the chlorofluorocarbons  reviewed
(CFCs  11, 12, 13, 112,  112a, 113, 113a, 114,  114a, 115)
are given in Table 1.

    Chlorofluorocarbons  are marketed under many different
trade  names,  e.g.,  Algcon, Algofrene,  Arcton, Eskimon,
Flugene, Forane, Freon, Frigen, Genetron, Isceon, Osotron,
Khladon. The individual chemical substances are character-
ized by code numbers, as defined in DIN 89 62,  which  are
very widely adopted and uniformly used.

2.1.1.  Technical product

    Commercial  chlorofluorocarbons rank among the highest
purity  organic chemicals sold  in the USA  (Bower, 1973),
the  purity of commercial  CFC-11 and CFC-12  commonly ex-
ceeding 99.9% (Hamilton, 1962). The predominant isomers of
the ethane series (CFC-113, CFC-114) are the more symmetri-
cal  ones  (CCl2F.CClF2  and CClF2.CC1F2). CFC-113 usually
contains  no more  than a  few tenths  of 1%  of  CFC-113a
(CCl3.CF3),      while  CFC-114  usually contains  no more
than  7-10%  CCl2F.CF3.  Levels  of other impurities in the
four  major CFCs (CFC-11,  CFC-12, CFC-113, CFC-114)  are:
moisture,  10 ppm; residue, a  few ppm; acids,  much  less
than  1 ppm;  and non-condensibles  (i.e., air components)
100-200 ppm  in the liquid  phase or 0.5-1.0%  in the  gas
phase (Hamilton, 1962).

    The  commercial chlorofluorocarbons may also be formu-
lated  with  chemicals other  than  CFCs, such  as actone,
ethanol, isopropanol, and methylene chloride. In addition,
nitromethane  or other stabilizers are  sometimes added to
alcohol-based aerosols (0.3% by weight) (Du Pont, 1980a).

Table 1.  Identity and physical and chemical properties of commercially
significant fully halogenated chlorofluorocarbonsa
Chemical formula      CCl3F           CCl2F2         CClF3           CC12F.CCl2F      CCl3.CClF2

Relative molecular    137.37          120.92         104.46          203.82           203.82
Common name           trichloro-      dichlorodio-   chlorotri-      1,2-difluoro-    1,1-difluoro-
                      fluoro-         fluormethane   fluoromethane   1,1,2,2-tetra-   1,2,2,2-    
                      methane                                        chloroethane     tetrachloro-

CAS registry number   75-69-4         75-71-8        75-72-9         76-12-0          76-11-9

Common synonyms       CFC-11, F-11,   CFC-12, F-12,  CFC-13, F-13    CFC-112, F-112   CFC-112a, 
and trade names       Freon 11,       Freon 12,                                       F-112a
                      Frigen 11,      Arcton, Frigen 12,           
                      Arcton 9        Genetron 12,
                                      Halon, Osotron 2

Physical state        liquid at       gas            gas             solid            solid
                      < 23.7 °C 

Colour                colourless      colourless     colourless      white

Odour                 faint ethereal  nearly         ethereal        slightly
                                      odourless                      camphor-like
Melting point (°C)    -111            -158           -181            26               40.6

Boiling point (°C)    23.82           -29.79         -81.4           92.8             91.5

Flashpointb           NF              NF             NF              NF               NF

Density of saturated  5.86            6.33           7.01            7.02
vapour at boiling     
point (g/litre)

Solubility in water   0.11            0.028          0.009           0.012
(25 °C) (wt %)                                                       (saturation pressure)

Conversion factor     5.71            5.03           4.34            8.47             8.47
(ppm(v/v)-> mg/m3) 
(20 °C)

Table 1 (contd.)

Chemical formula      CCl2F.CClF2     CCl3.CF3       CClF2.CClF2     CCl2F.CF3        CClF2.CF3

Relative molecular    187.38          187.38         170.92          170.92           154.47

Common name           1,1,2-tri-      1,1,1-tri-     1,2-dichloro-   1,1-dichloro-    1-chloro-1,1,
                      chloro-1,2,2-   chloro-2,2,2-  1,1,2,2-tetra-  1,2,2,2-tetra-   2,2,2-penta-
                      trifluoro-      trifluoro-     fluoroethane    fluoroethane     fluoroethane
                      ethane          ethane

CAS registry number   76-13-1         354-58-5       76-14-2         374-07-2         76-15-3

Common synonyms       CFC-113, F-113  CFC-113a       CFC-114,        CFC-114a,        CFC-115, F-115
and trade names       Freon 113                      F-114           F-114a           Freon 115

Physical state        liquid          liquid         gas             gas              gas

Colour                colourless                     colourless                       colourless

Odour                 nearly                         nearly          
                      odourless                      odourless

Melting point (°C)    -35             14.2           -94             -94              -106

Boiling point (°C)    47.57           45.8           3.77            3.6              -39.1

Flashpointb           NF              NF             NF              NF               NF

Density of saturated  7.38                           7.83                             8.37
vapour at boiling 
point (g/litre)

Solubility in water   0.011                          0.009                            0.006
(25 °C) (wt %)

Conversion factor     7.79            7.79           7.11            7.11             6.42
(ppm(v/v) -> mg/m3) 
(20 °C)
a  From: Du Pont (1980b); Smart (1980); Hawley (1981); and Windholz (1983).
b  NF: non-flammable.
2.2.  Physical and chemical properties

    Chlorofluorocarbons  are usually characterized by high
vapour  pressure (low boiling  point) and density  and low
viscosity,  surface  tension, refractive  index, and solu-
bility  in water. The common physical and chemical proper-
ties  of the commercially  significant chlorofluorocarbons
are given in Table 1.

    The  degree  of fluorine  substitution greatly affects
the  physical  properties of  chlorofluorocarbons. In gen-
eral, as the number of fluorine atoms  replacing  chlorine
increases,  the  vapour  pressure also  increases, but the
boiling  point, density, and solubility in water decrease.
For  example,  in  the chlorofluoroethane  series,  vapour
pressure increases with fluorination in the sequence:

    CFC-112 < CFC-113 < CFC-114 < CFC-115 < CFC-116

    The  solvent  power of  the chlorofluorocarbons ranges
from poor for the highly fluorinated compounds  to  fairly
good  for the less fluorinated compounds (Du Pont, 1980b).
Being  typical non-polar liquids,  they exhibit low  water

    Apart  from their use  as chemical intermediates,  the
chlorofluorocarbons   reviewed   find  applications   that
reflect  their  chemical  stability rather  than  chemical
reactivity.   This chemical stability  is a result  of the
strength of the C-F bond (Bower, 1973).

    Although  quite inert, chlorofluorocarbons  do exhibit
some   chemical  reactivity  in  some  applications.   For
example,  although they exhibit  a low rate  of hydrolysis
compared  with  other  halogenated compounds,  the rate of
hydrolysis  is greatly affected by  temperature, pressure,
the  presence of metals,  and the pH  of the solution  (Du
Pont,  1980a,b).  Thus CFC-11 is considered unsuitable for
water-based  products  packaged in  metal containers since
some  metals may catalyse  the hydrolysis of  CFC-11  with
liberation  of  acid.   Sanders (1960)  has demonstrated a
free-radical   reaction   between   CFC-11  and   alcohols
resulting  in dichloromonofluoromethane and  small amounts
of  tetrachlorodifluoroethane.  The reaction  is inhibited
by  high concentrations of  oxygen and, therefore,  it  is
unlikely  that it  will occur  in nature.   In some  cases
dechlorination  by zinc (also by  magnesium and aluminium)
can occur in the presence of polar solvents:

  FCl2C-CClF2  ->  FClC=CF2  +  ZnCl2

    Chlorofluorocarbons  are highly resistant to attack by
conventional  oxidizing  agents  at  temperatures  <200 °C
(Downing,  1966; Bower, 1973).  In general, they exhibit a

high  degree  of  thermal stability,  but  when  pyrolysis
occurs  in the presence  of humidity the  products usually
include  hydrofluoric  and  hydrochloric acid  and, in the
presence of either water or oxygen, phosgene.

    The  photolysis of chlorofluorocarbons is discussed in
section 4.2.3.

    The  carbon-fluorine bonds in  chlorofluorocarbon com-
pounds  are  extremely  resistant to  almost  all chemical
reagents.   Reduction with hydrogen  does not occur  until
temperatures are >830 °C, and often the C-C bond  is  also
cleaved.  Strong reducing agents such as lithium aluminium
hydride  will not reduce the C-F bond. However, chloroflu-
orocarbons  react violently with alkali and alkaline earth
metals,  such  as  sodium, potassium,  and  barium (Bower,

2.3.  Conversion factors

    Conversion  factors  for  the chlorofluorocarbons  re-
viewed in this monograph are given in Table 1.

2.4.  Analytical methods

    Several  analytical  procedures used  for the determi-
nation  of chlorofluorocarbons are summarized  in Table 2.
Methods used include spectrophotometry, gas chromatography
with  several  quantification  procedures, and  mass spec-
trometry.   However,  the  majority  of  methods  use  gas
chromatography with various detection techniques.  Methods
for  sample  collection  have been  developed  to  achieve
greater selectivity and sensitivity.

Table 2.  Analytical methods for the determination of chlorofluorocarbons
Sample     Samping method/clean-up        Analytical method               Detection   Reference
type                                                                      limit 
Air                                       modified inlet with silicon     100 ppb     Collins &             
                                          rubber membrane;                            Utley (1972)
                                          mass spectrometry

Air                                       gas chromatography - electron   50-100 ppb  Collins et 
                                          capture detection                           al. (1965)

Air                                       gas chromatography - electron   5-10 ppt    Lovelock et 
                                          capture detection                           al. (1973);
                                                                                      Su & Goldberg 
                                                                                      (1973); Hester 
                                                                                      et al. (1974)

Air        sorption on cold (< -50 °C)   gas chromatography - electron   1 ppt       Paryjczak et 
           activated carbon               capture detection                           al. (1985)          

Air        sorption on cold (< -50 °C)   gas chromatography - electron   1 ppt       Reineke & 
           Tenax-TA+ activated carbon     capture detection                           Baechmann (1985)

Air        cryogenic trapping in porous   gas chromatography - electron   1 ppt       Rudolph & Jebsen 
           glass beads                    capture detection                           (1983)          

Air        sorption on cold (liquid       gas chromatography - electron   1 ppt       Singh et al. 
           N2) SE-30/glass wool           capture detection                           (1983)

Air        sorption on cold (-40 °C)      gas chromatography - electron   1 ppt       Makide et al. 
           OV-101                         capture detection                           (1980)
Air        sorption on cold (< -50 °C)   gas chromatography -            2.6 ppt     Crescentini 
           activated carbon               high-resolution                             et al. (1983)
                                          mass spectrometry                                  

Table 2.  (contd.)
Sample     Samping method/clean-up        Analytical method               Detection   Reference
type                                                                      limit 

Air                                       absorption spectrometry using               Zasavitskii 
                                          diode laser                                 et al. (1984)

Air        sorption on Tenax GC/          capillary column gas                        Hanai et al. 
           activated carbon               chromatography - electron                   (1984)
                                          capture detection                               

Air                                       spectrophotometry of pyridine   7 ppm       Tyras (1981)
(occupational)                            complex

Sea water  dynamic purge and trap         gas chromatography - electron   0.003 ng/   Bullister & 
                                          capture detection               litre       Weiss (1983)

Blood      head space                     gas chromatography - electron   0.01-0.01   Ramsey & 
                                          capture detection               ng/litre    Flanagan 

3.1.  Natural occurrence

    The  chlorofluorocarbons  discussed in  this monograph
are not known to occur in nature.

3.2.  Man-made sources

    Almost  all  chlorofluorocarbons produced,  except for
those  used  as  chemical  intermediates,  are  eventually
released into the environment, whether during manufacture,
handling,  use,  or  disposal.  The  significance  of  the
release  mechanisms  discussed  below should  be evaluated
with this in mind.

3.2.1.  Production levels

    The  estimated world production of the three important
potentially  ozone-depleting  chlorofluorocarbons (CFC-11,
CFC-12, and CFC-113) in 1985 was approximately one million
tonnes, about 30% being in the USA (SRI,  1986).   Table 3
indicates  some of the major world producers in 1985 (CMA,
1986; CMR, 1986; Rand, 1986; SRI, 1986).

    The  reported total demand for all chlorofluorocarbons
in the USA in 1985 was 458 000 tonnes (CMR, 1986),  a  26%
increase  from the demand figure in 1980 (CMR, 1981). Pro-
duction figures for CFC-11, CFC-12, and CFC-113 in the USA
for  1974-1985 are given in Table 4.  In 1984, these three
CFCs  accounted for 83%  of the total  chlorofluorocarbons
produced  in the USA  (US ITC, 1985).   Based on the  1980
demand  and the strong  market position in  several appli-
cations,  CMR (1986) projected that the demand for chloro-
fluorocarbons in the USA would grow to  458 000 tonnes  in
1985 and reach 590 000 tonnes by 1990, a  positive  growth
in this 5-year period of 5% per year.  However,  this  was
before  the  Montreal  Protocol was  signed  in  September
1987.a     The demand for CFC-11, which is used mainly for

a The Montreal Protocol on Substances that Deplete the 
  Ozone Layer, signed by 24 countries in September 1987,  
  requires a 20% reduction in use and production of the  
  chlorofluorocarbons 11, 12, 113, 114, and 115 from 1 
  July 1993 and a further 30% reduction from 1 July 1998. 
  It stipulates a number of stepwise importation bans 
  binding on signatories in order to achieve these 
  reductions (United Nations Environment Programme.  
  Montreal Protocol on Substances that Deplete the Ozone 
  Layer, Final Act, Montreal, 1987). 

foam blowing, was largely anticipated to follow the expan-
sion pattern of the construction industry. Demand for flu-
oropolymers  made from CFC-113  (as well as  from HCFCs 22
and  142b) is expected to  grow at a rate  of 10% or  more
because  of  electrical and  electronic applications.  The
demand for CFC-113 is also expected to grow because of its
use as a solvent in the semi-conductor industry and  as  a
replacement  for  chlorinated  solvents  under  regulatory
pressure  (CMR,  1986). Between  1964  and 1974,  the pro-
duction  of CFC-11 and  CFC-12 increased at  8 and 9%  per
year  respectively.   At  that time,  the  hypothesis that
certain  chlorofluorocarbons that accumulate in  the upper
atmosphere  could deplete the  earth's ozone layer  had  a
major impact on the fluorochemical industry (Smart, 1980).

The  US EPA (1978) ruled  that most aerosol products  con-
taining CFC-11 and CFC-12 propellants could not  be  manu-
factured  in the USA after 15 December, 1978. As a result,
the  production of CFC-11 and CFC-12 fell sharply, stabil-
izing  in 1980.  However, with the entry into force of the
Montreal  Protocol,  which progressively  limited the pro-
duction  of CFCs-11, 12, 113, 114, and 115, the release of
all of these chlorofluorocarbons should decline.

Table 3.  Some of the major world producers of chlorofluorocarbons 
in 1985a,b
Country       Company name
Argentina     Ducilo S.A. (subsidiary of Du Pont de Nemours and Co.)

Australia     Pacific Chemical Industries Pty. Ltd. (subsidiary of 
              Atochem S.A.); Australian Fluorine Chemical Pty. Ltd. 

Brazil        Du Pont do Brasil S.A. (subsidiary of Du Pont de Nemours 
              and Co.); Hoechst do Brasil Quimica e Farmacêutica S.A. 
              (subsidiary of Hoechst A.G.) 

Canada        Allied Canada, Inc. (subsidiary of Allied Corp.); Du Pont 
              Canada Inc. 

France        Atochem S.A.

Germany,      Hoechst AG (Frigen); Kali-Chemie AG (Kaltron)
Republic of

Greece        Société des Industries Chimiques du Nord de la Grèce, S.A. 

India         Navin Fluorine Industries

Italy         Montefluos S.p.A. (Algofren)

Japan         Asahi Glass Co., Ltd. (Asahiflon); Daikin Kogyo Co., Ltd. 
              (Daiflon); Du Pont Mitsui Fluorochemical Co., Ltd. (Flon) 
              Showa Denko, K.K. 

Mexico        Quimoleasicos, S.A. (subsidiary of Allied Corp.); 
              Halocarburos S.A. (subsidiary of E.I. Du Pont de Nemours 
              and Co., Inc.) 

Netherlands   Akzochemic B.V.; Du Pont de Nemours (Nederland) B.V. 
              (subsidiary of E.I. Du Pont de Nemours and Co., Inc) 

Spain         Ugimica S.A. (subsidiary of Atochem, S.A.); Hoechst 
              Iberica (subsidiary of Hoechst AG); Kali-Chemie S.A. 
              (subsidiary to Kali-Chemie AG) 

United        Imperial Chemical Industries PLC (Arcton); I.S.C. 
Kingdom       Chemicals Ltd. (Isecon)

USA           Allied Corp.; E.I. Du Pont de Nemours and Co. Inc.; Essex 
              Chemical Corp.; Kaiser Aluminum and Chemical Corp.; 
              Pennwalt Corp. 

Venezuela     Produren (subsidiary to Atochem, S.A.)
a  From: CMA (1986); CMR (1986); and SRI (1986).
b  Trade names are given in parentheses, where available.
    From: Noble (1972) and Smart (1980).

Table 4.  Production of the major chlorofluorocarbons 
in the USA in thousands of tonnesa
Year    CFC-11    CFC-12     CFC-113b
1985    73.9b,c   127.9b,c   73.2c
1984    83.9      152.7      65.9d
1982    63.6      117.0      NA
1980    71.7      133.8      NA
1979    75.8      133.3      NA
1978    87.9      148.4      NA
1977    96.4      162.5      >23.1
1976    116.2     178.3      NA
1975    122.3     178.3      NA
1974    154.6     221.1      29.0
a   From: US ITC (1975-85), unless otherwise specified.
b   From: Smart (1980), US EPA (1980), and Rand (1986).
c   It is assumed that consumption was the same as 
    production volume.
d   Estimated value from the 1985 production data and 
    the assumption that the 1984 production volume was 
    10% lower (CMR, 1986).
NA  = Not available.

3.2.2.  Manufacturing processes

    The  traditional  method  for manufacturing  the fully
halogenated chlorofluorocarbons is the catalytic displace-
ment of chlorine from chlorocarbons with fluorine by reac-
tion  with  anhydrous  hydrogen fluoride  (Hamilton, 1962;
Smart,  1980).  Carbon tetrachloride, and hexachloroethane
(or  tetrachloroethylene plus chlorine) are  commonly used
starting  materials  for 1- and  2-carbon chlorofluorocar-
bons.  Carbon tetrachloride is normally used for producing
CFC-11,  CFC-12, and CFC-113.   The reaction can  occur in
either liquid or vapour phases. The processes use antimony
pentafluoride  or an equivalent catalyst,  in contact with
which the chlorocarbon and hydrogen fluoride react. Excess
hydrogen fluoride may then be recovered and the chloroflu-
orocarbon stream is neutralised to remove traces  of  acid
and  dried.  The chlorofluorocarbons are then separated in
a fractionating column and sent to storage. An alternative
process for the production of the methane-based chloroflu-
orocarbons  uses  the direct  reaction  of methane  with a
mixture  of chlorine and hydrogen  fluoride (Noble, 1972).
Other commercially important chlorine-fluorine-substituted
hydrocarbons   are   manufactured  by   similar  processes
(Lowenheim & Moran, 1975).

    The  production  processes  described above  give very
high yields.  Losses of chlorofluorocarbons are limited to
small  mechanical leakage, small amounts  leaving with the
by-product  hydrogen chloride, and  miscellaneous venting.
The  total  material loss  is estimated to  be 1% at  most

(McCarthy,  1973) for the production  operations excluding
transport  and storage.  Fuller  et al. (1976)  assumed  a
total  production loss of  1.5% for the  commercially pro-
duced chlorofluorocarbons.

3.2.3.  Loss during disposal of wastes

    The  release of chlorofluorocarbons into  the environ-
ment  during their disposal arises  mainly from pre-fabri-
cated   refrigeration   and  air-conditioning   equipment.
Environmental   contamination  due  to  chlorofluorocarbon
disposal results principally from the following:

*   Unreclaimed  refrigerants  in  the cooling  systems of
    scrapped  pre-fabricated-type  refrigeration and  air-
    conditioning  units.  Disposal of these old appliances
    is usually to scrap yards or waste dumps.  Efforts are
    made  in  some countries  to remove chlorofluorocarbon
    refrigerants before discarding equipment.

*   Discarding  of vessels containing unused chlorofluoro-

*   Time-release   of  trapped  blowing  agents  in  rigid
    urethane  products. This is a minor source of environ-
    mental  contamination  compared with  that of scrapped

    Waste  disposal  streams resulting  from manufacturing
operations  are very minor contamination  sources compared
with scrapped refrigerants.

    Because  of the high vapour  pressure of chlorofluoro-
carbons  at ambient temperature, all releases pass eventu-
ally  into the atmosphere except  in cases where the  com-
pounds have been chemically altered.

3.2.4.  Release from transport, storage, and accidents  Transport and storage

    The  principal factor required  for the transport  and
storage  of  the  major  chlorofluorocarbons  is  adequate
design to meet the elevated pressures.  The  products  are
shipped in a wide variety of pressure  containers  ranging
from 23-litre drums to 91-m3 tank cars.

    The  containers are fitted with safety valves, rupture
discs,  and  fusible  plugs  according  to  US  Interstate
Commerce  Commission  (ICC) specifications;  also included
are requirements for labelling and leak pressure testing.

    Loss  of product during transport and storage is rela-
tively minor because of the completely closed system used.
Losses are further controlled by monitoring discrepancies,

if  any,  between  product  billings  and  receipts.    In
addition, the high cost of the products provides an incen-
tive to control losses.  The total industry-wide  loss  in
transport  and storage is <1%  of the total quantity  pro-
duced.  Accidents

    Data  concerning  accidental  release are  not readily
available.  However,  it  is probable  that quantities re-
leased by accident are negligible compared with quantities
released by use and disposal.

3.3.  Use patterns

3.3.1.  Major uses

    Chlorofluorocarbons are commercially important because
of their unique physical and chemical properties and rela-
tively  low physiological activity.  They  are mainly used
as  refrigerants,  solvents,  blowing agents,  sterilants,
aerosol  propellants,  and as  intermediates for plastics.
Table 5  lists the estimated use patterns of chlorofluoro-
carbons  in the USA  for the years  1975, 1978, 1981,  and
1985.   The aerosol propellant market, which consumed half
of  the  total  chlorofluorocarbon production  in 1975, is
currently  a  minor  application because  of  governmental

    Estimated use patterns of CFC-11 and CFC-12 in the USA
and  worldwide (excluding eastern European  countries) are
given  in Tables 6 and  7, respectively (Rand,  1986). The
"unallocated"  amounts represent the  difference between
the amount of estimated use and the total production data.
According to Rand (1986), part of the unallocated use con-
sists  of  unreported  food refrigeration  use  and losses
during storage, packaging, and transport.

    In  countries that signed  the Montreal Protocol,  the
use of these chlorofluorocarbons will decline.

3.3.2.  Release from use: controlled or uncontrolled

    The release of CFC-11 and CFC-12 during use has caused the  greatest  
concern  environmentally because  of  their impact  on  ozone-depletion.   
During the  mid-1970s, when aerosol  propellant  use was  the major 
chlorofluorocarbon application,  aerosols accounted for 75%  of the 
immediate release  of  CFC-11  and CFC-12,  while  refrigerants  and 
blowing  agents  accounted  for 14%  and 12%, respectively (Smart,  
1980).   Table 8  shows the  estimated release of these  two 
chlorofluorocarbons in 1965,  1970, 1975, 1980, and  1985.  CMA (1986) 
estimated that the total cumulative worldwide   (with   the  exception   
of  eastern  European countries)  release of CFC-11  and CFC-12 as  a 
result  of their  use since 1931  amounted to 13.6 million  tonnes in 

Table 5.  Estimated use patterns of chlorofluorocarbons 
in the USAa  (% total production)
Application                   1975  1978  1981  1985
Aerosol propellants           50    24    <1    2
Refrigerants                  28    39    46    39
Foam blowing agents            b     12    20    17
Solvents                      5     11    16    14
Plastics and resins           10     b     7     14
Sterilant gas                  b      b     2     2
Food freezant                  b      b     1     1
Miscellaneous and export      7     14    7     11
a   From: CMR (1975, 1978, 1981, 1986).
 b   Included in miscellaneous category.

Table 6.  Estimated use patterns of CFC-11 in the USA and worldwidea
(excluding eastern European countries)
Use                         USA                World
Blowing agent               71%                 58%
Refrigeration                6%                  3%
Aerosol                      5%                 31%
Miscellaneous               18%                  8%
a   From: Rand (1986).

Table 7.  Estimated use patterns of CFC-12 in the USA 
and worldwidea (excluding eastern European countries)
Use                         USA    World
Blowing agent               11%    12%
Mobile air-conditioning     37%    20%
Retail food refrigeration   4%     3%
Chillers                    1%     1%
Home refrigerators          2%     3%
Aerosol                     4%     32%
Miscellaneous               10%    7%
Unallocated                 31%    22%
a   From: Rand (1986).

Table 8.  Worldwide production and release of CFC-11 and CFC-12 during use 
(thousands of tonnes)a
                                               Release from:
Year   Production   Refrigeration   Refrigeration   Blowing agent  Other     Total
                    (hermetically-  (non-hermetic)  (closed-cell   sources   release
                    sealed)                         foam only)
1965   312.9        0.8             44.9            5.7            232.1     283.5
1970   559.2        1.2             68.5            16.3           420.7     506.7

1975   695.1        1.8             103.8           35.4           574.0     715.0

1980   639.8        2.6             156.1           65.0           359.7     583.4

1985   703.1        3.9             188.2           99.4           357.8     649.3
a   From: CMA (1986).

4.1.  Transport between media

    Because  of the high vapour  pressure of chlorofluoro-
carbons, the major transport medium is the atmosphere. For
example,  Lovelock (1972) found that CFC-11 concentrations
in  rural  southern England  and  Ireland could  be partly
attributed to sources on the continent of Europe.

    CFC-11 and CFC-12 introduced into aquatic systems will
most  likely volatilize to  the atmosphere.  Once  in  the
troposphere, they will eventually diffuse into the strato-
sphere  or be carried back  to the earth through  precipi-
tation (Callahan et al., 1979).

    Data pertaining to the adsorption of CFC-11 and CFC-12
onto  soils  and  sediments are  inconclusive (Callahan et
al.,  1979).   However, the  octanol/water partition coef-
ficients  of  CFC-11  (log P = 2.53) and  CFC-12  (log P =
2.16)  (Hansch et al., 1975) indicate that adsorption onto
organic particulates may be possible. In cases of signifi-
cant sorption to soils, the volatilization of  these  com-
pounds will be slower than in aquatic systems, though vol-
atilization  may still be the major transport process from

4.2.  Environmental transformation and degradation processes

4.2.1.  Oxidation

    No  information is available concerning  the oxidation
of CFC-11 or CFC-12 in the aquatic environment under ambi-
ent conditions. These two chlorofluorocarbons are known to
be  relatively stable with  respect to attack  by hydroxyl
radicals present in the troposphere (Lillian et al., 1975;
US EPA, 1975; Cox et al., 1976; Hanst, 1978).

4.2.2.  Hydrolysis

    As  a group, chlorofluorocarbons exhibit a low rate of
hydrolysis  compared with other halogenated compounds, and
the rates of hydrolysis are greatly affected  by  tempera-
ture,  pressure, and the  presence of catalytic  materials
such  as metals.  Should hydrolysis of CFC-12 and possibly
other  chlorofluorocarbons  occur,  it would  proceed at a
negligible  rate compared with the  rate of volatilization
and subsequent photodissociation.

4.2.3.  Photolysis  Photochemistry

    Atmospheric  ozone prevents virtually all  sunlight of
wavelengths  less  than  290 nm from  reaching the earth's

surface.   Since the wavelength  of sunlight at  altitudes
below  50 km is greater  than 280 nm, which  is above  the
wavelength absorbed by chlorofluorocarbons (Doucet et al.,
1973,  1974), there is no mechanism for direct photoalter-
ation of these chemicals in the lower atmosphere.  Environmental transformation

    CFC-11 and CFC-12 do not photodissociate in the tropo-
sphere,  since they do not absorb radiation at wavelengths
greater than 200 nm (Hanst, 1978). They eventually diffuse
into  the stratosphere (NRC, 1976; Hanst, 1978) where they
are  broken  down  by higher  energy,  shorter  wavelength
ultraviolet  radiation  (Jayanty  et al.,  1975; Rebbert &
Ausloos,  1975;  US  EPA,  1975;  Hanst,  1978;  Isaksen &
Stordal, 1981).

    The photodissociation of CFC-11 and CFC-12 each result
in the release of two chlorine atoms, since less energy is
required  to  cleave  the  C-Cl  bond  than  the  C-F bond
(Rebbert  & Ausloos, 1975).   According to Jayanty  et al.
(1975),  the photolysis of CFC-11 in the presence of  O2 at
213.9 nm and 25 °C leads to the production of  CFClO  and,
potentially,  chlorine  molecules (Cl2),    while the pho-
tolysis of CFC-12 under the same conditions leads  to  the
production  of CF2O   and Cl2.    Chlorine atoms, released
by  reactions such as these, are catalysts in the destruc-
tion  of  the stratospheric  ozone  layer (US  EPA,  1975;
Hanst, 1978; Ember, 1986; Zurer, 1988).

    Isaksen   &  Stordal  (1981)  rationalized  the  ozone
depletion  by way of  a cycle involving  the  intermediate
formation of chlorine oxide (ClO).  The net  reaction  for
each turn of the cycle is as follows:

         Cl + O3     ->   ClO + O2
        ClO + O      ->    Cl + O2
    Net   O + O3     ->     2O2

Other  sequences involving ultraviolet radiation  and rad-
ical species have also been proposed (Ember, 1986).

4.2.4.  Biodegradation

    No  information on the biodegradability of the commer-
cial  chlorofluorocarbons  is  available (Su  &  Goldberg,
1976; Callahan et al., 1979).

4.3.  Interaction with other physical, chemical, or biological factors 

    As indicated above, the commercial chlorofluorocarbons
are  relatively persistent in  the environment because  of
their  chemical stability, although  their degree of  per-
sistence  has  not  been determined  with  accuracy.   The

current  best estimates for the average residence times in
the  atmosphere are 65, 110,  400, 90, 180, and  380 years
for  CFC-11,  CFC-12,  CFC-13, CFC-113,  CFC-114, and CFC-
115, respectively (NASA, 1986).

    Assuming  a troposphere-to-stratosphere turnover  time
(the time taken for 63% of troposphere air to diffuse into
the  stratosphere) of 30 years, tropospheric life-times of
65  and 110 years, respectively, would result in about 86%
of  tropospheric CFC-11 and CFC-12 eventually reaching the
stratosphere.  The effect of the transport of  CFC-11  and
CFC-12  from troposphere to stratosphere has been reviewed
by  NASA (1986).  The addition of CFC-11 and CFC-12 to the
atmosphere affects the climate in two ways. Firstly, these
compounds  have strong absorption bands in the atmospheric
"window"  region, that is from 7-13 µm.  Therefore, both
CFC-11  and CFC-12 will  induce a "greenhouse"   warming
effect by direct absorption of terrestrial radiation.  The
second effect is due to the depletion of the stratospheric
ozone layer. Mathematical modelling has shown that chloro-
fluorocarbons will reduce the ozone column.  For instance,
it  has been calculated  that a chlorofluorocarbon  growth
rate  of 3% per year  would lead to a  10% ozone depletion
within  70 years (NASA, 1986).  Changes of that magnitude,
or  even  smaller  ones, could  have  important biological
consequences (sections 6 and 9.4). Additions of chloroflu-
orocarbons  to the atmosphere are also predicted to modify
the vertical distribution within the ozone column.   As  a
result of the unique regional meteorology and the presence
of   chlorine  radicals  in  the  Antarctic  stratosphere,
stratospheric   ozone  reductions  of  30-50%   have  been
recently observed there during the austral spring.

    The  reduction of stratospheric ozone affects the sur-
face in two ways:

*   directly  by increasing the penetration of ultraviolet
    B radiation (290-320 nm);

*   indirectly by enhancing the global warming effects and
    altering climatic conditions.

4.4.  Bioconcentration and bioaccumulation

    Dickson  & Riley (1976) have found CFC-11 at levels of
0.6-28 µg/kg  (dry weight basis) in various organs of fish
and  molluscs.  These levels, however,  do not necessarily
indicate a potential for bioaccumulation.

    Neely  et al. (1974) suggested that bioaccumulation is
directly  related  to  the octanol/water  partition  coef-
ficient (P) of the compound. The experimentally determined
log octanol/water partition coefficients (log P) of CFC-11
and  CFC-12 (see section 4.1.1)  indicate that the  bioac-
cumulation potential in organisms is low.


5.1.  Environmental levels

5.1.1.  Air

    Singh  et  al.  (1979) collected in  situ air  samples
aboard  a US Coast  Guard vessel that  sailed the  Pacific
Ocean from Oakland, California, USA (37 °N) to Wellington,
New Zealand (42 °S). Tyson et al. (1978) made measurements
at  latitudes from 74 °N to  62 °S as part of  a 1976 NASA
Latitude  Survey  Mission  between Alaska,  USA,  and  New
Zealand.   The results of their  monitoring are summarized
in Table 9.
Table 9.  Global distribution of chlorofluorocarbons in the troposphere (ng/m3)a
               Northern hemisphere           Southern hemisphere     

Chloro-        Mean          Standard        Mean          Standard     Reference
fluorocarbon                 deviation                     deviation
CFC-11         747.5 (113)   75.3 (13.4)     668.8 (119)   65.8 (11.7)  Singh et al. (1979)
               741.8 (132)   50.6 (9)        696.9 (124)   33.7 (6)     Tyson et al. (1978)

CFC-12         1138.5 (230)  126.2 (25.5)    1039.5 (210)  124.2 (25.1) Singh et al. (1979)
               1079.1 (218)  54.4 (11)       821.7 (166)   39.6 (8)     Tyson et al. (1978)

CFC-113        145.9 (19)    26.8 (3.5)      138.1 (18)    23.8 (3.1)   Singh et al. (1979)

CFC-114        83.9 (12)     13.3 (1.9)      69.9 (10)     9.1 (1.3)    Singh et al. (1979)
a  Figures in brackets are in parts per trillion (by volume).

    The  increased use of chlorofluorocarbons  on a world-
wide  basis has  resulted in  an increase  in  the  global
levels of these compounds. The two most  abundant  chloro-
fluorocarbons  in  the  atmosphere are  CFC-11  and CFC-12
(Guicherit & Schulting, 1985).  The annual growth rates in
the 1980s appear to be slower than the growth rates in the
1970s  (Rasmussen et al.,  1981). The annual  rate of  in-
crease in CFC-11 global levels during the period 1975-1980
was  8-12% (Rasmussen et al.,  1981; Fraser et al.,  1983;
Singh  et al., 1983), whereas it was 6-7% during 1980-1981
(Brice  et al., 1982; Cunnold et al., 1983b; Prinn et al.,
1983;  Rasmussen & Khalil, 1986).  Similarly, although the
average  annual growth rate  for global levels  of  CFC-12
during 1975-1980 was 8-9% (Rasmussen et al.,  1981;  Singh
et  al., 1983), it  was only 6%  in 1980 (Cunnold  et al.,
1983b; Prinn et al., 1983; Rasmussen & Khalil, 1986). Both
CFC-11 and CFC-12 showed an accumulative increase of about
60%  during  the  decade 1975-1985  (Rasmussen  &  Khalil,

    Data  on the atmospheric concentrations of chlorofluo-
rocarbons  are shown in Table 10.   Measurements of atmos-
pheric chlorofluorocarbon concentrations up to an altitude
of  6 km  did  not reveal  any  significant  concentration
changes  with  increasing  altitude (Rasmussen  &  Khalil,
1982, 1983, 1986; Robinson et al., 1983).  Hunter-Smith et
al.  (1983), Rasmussen & Khalil  (1983), and Singh et  al.
(1983)  studied the latitudinal variation in chlorofluoro-
carbon  concentrations  between the  northern and southern
hemisphere and reported inter-hemispheric contrasts (ratio
of  concentration  between  northern  and  southern  hemi-
spheres)  of  1.08  for  CFC-11,  1.07-1.08  for   CFC-12,
1.10-1.25  for  CFC-113,  and 1.08  for CFC-114.  Table 10
reveals that the concentrations of chlorofluorocarbons are
higher in urban areas than in remote areas, this being the
result of local emission sources. The urban concentrations
of chlorofluorocarbons (CFC-11 and CFC-12) in the People's
Republic  of China, with the exception of Beijing, are the
same as background levels in the USA. This is probably due
to  the less  extensive use  of these  compounds in  urban
areas in China (Rasmussen et al., 1982).

    Median  concentrations of the most abundant compounds,
CFC-11  and  CFC-12,  in several  urban/suburban areas and
rural/remote  areas in the  USA are reported  in  Table 10
(Brodzinsky  & Singh, 1982).  These measurements were made
from 1972 to 1980, the median year being 1975. Median con-
centration  values of 1090 and 3420 ng/m3 for  CFC-11, and
1630  and  5700 ng/m3 for   CFC-12,  in  rural/remote  and
urban/suburban  areas,  respectively,  were projected  for
1985,  assuming that the  average annual growth  rate  for
both compounds would be 5% (NASA, 1986).  Assuming that an
individual  inhales  20 m3 air/day,  the  total inhalation
exposure  (CFC-11 plus  CFC-12) in  1985 would  be  54  or
182 µg/day  in rural/remote or urban/suburban areas of the
USA, respectively.  Using the 1985 data from Ragged Point,
Barbados, as a basis, the inhalation for  combined  CFC-11
and CFC-12 in rural/remote areas in late 1985  would  have
been 66 µg/day.
Table 10.  Some worldwide measurements of the atmospheric
concentrations of chlorofluorocarbons
                                        Concentration of                            
Location                 Year      chlorofluorocarbons (ng/m3)    Reference
                                CFC-11  CFC-12  CFC-113  CFC-114

 Ragged Point            1980   NR      1499    NR       NR       Cunnold et al. (1983b)

                         1985   1313    2012    NR       NR       NASA (1986)

 Samoa (American) 

 Point Matatula          1980   NR      1433    NR       NR       Cunnold et al. (1983b)

Table 10. (contd.)
                                        Concentration of                            
Location                 Year      chlorofluorocarbons (ng/m3)    Reference
                                CFC-11  CFC-12  CFC-113  CFC-114
 United Kingdom 

 Harwell                 1980   1342    NR      NR       NR       Brice et al. (1982)

 Adrigole, Ireland       1980   NR      1564    NR       NR       Cunnold et al. (1983b)


 Phoenix, Arizona        1979   1423    NR      1192     NR       Singh et al. (1981)

 Los Angeles,            1979   2700    NR      2376     NR       Singh et al.  (1981)

 Oakland, California     1979   1365    NR      381      NR       Singh et al. (1981)

 USA rural/remote        1973-  685     1911    241      64       Brodzinsky & Singh (1982)
 (median concentration)  1980

 USA urban/suburban      1972-  1199    3521    1324     199      Brodzinsky & Singh (1982)
 (median concentration)  1980

 Pacific Northwest       1980   1073    1620    132      NR       Rasmussen et al. (1981)

Northern hemisphere      1978   919     1378    101      NR       Rasmussen & Khalil (1982)

Northern hemisphere      1978   1062    1534    179      100      Singh et al. (1983)

Southern hemisphere      1978   845     1283    93       NR       Rasmussen & Khalil (1982)

Southern hemisphere      1978   982     1418    164      92       Singh et al. (1983)

Arctic                   1982   1174    1780    175      NR       Rasmussen & Khalil (1983)

Arctic haze              1979   1097    1633    NR       NR       Khalil & Rasmussen (1983)

South Pole               1980   948     1428    86       NR       Rasmussen et al. (1981)

Over Atlantic Ocean      1981   1056    NR      NR       NR       Brice et al. (1982)

Global average           1980   959     NR      NR       NR       Fraser et al. (1983)
NR = not reported.
5.1.2.  Water

    Singh et al. (1979) measured CFC-11 and CFC-12 concen-
trations  in  1977 at  various  locations in  the  Pacific
Ocean.   The average surface  concentration of CFC-11  was
0.13 (± 0.006) ng/litre,  while  the CFC-12  concentration

was 0.28 (± 0.15) ng/litre.  The average concentrations at
a  depth of 300 m were  0.06 and 0.21 ng/litre for  CFC-11
and CFC-12, respectively. The concentrations of CFC-11 and
CFC-12 at various locations in the eastern  Pacific  Ocean
(surface  waters)  during  1979-1981 were  0.22  and  0.25
ng/litre  (Singh et al.,  1983), in Greenland  Sea surface
water  in 1982 were  0.61 and 0.21 ng/litre  (Bullister  &
Weiss,   1983),  and  in  Japanese   coastal  waters  were
0.20-0.54  and 0.19-0.33 ng/litre, respectively (Tomita et
al., 1983).

    Samples of water from Lake Ontario analysed  for  vol-
atile  halocarbon  contaminants  contained  mean   concen-
trations  for CFC-11 and  CFC-12 of 249  and 572 ng/litre,
respectively  (Kaiser et al., 1983).   An alluvial aquifer
in  Southington, Connecticut, USA, adjacent  to a solvent-
recovery  operation  was  analysed in  1980  for  volatile
organic  compounds, but CFC-12 was not detected (detection
limit not specified) in water obtained from various depths
(Hall, 1984). CFC-11 and CFC-12 have been detected in sur-
face snow and rainwater in Alaska (Su &  Goldberg,  1976).
The detection of chlorofluorocarbons in drinking-water has
not been reported.

5.1.3.  Food and other edible products

    With the exception of a few scattered reports (section
4.4), chlorofluorocarbons have not been measured in food.

5.2.  Occupational exposure

    Information  on occupational exposure is summarized in
section 9.2.


6.1.  Introduction

    Speculation  on the possibility of stratospheric ozone
reduction first appeared in the early 1970's  and  focused
on the consequences of large quantities of nitrogen oxides
being  injected  into  the upper  atmosphere by supersonic
aircraft flying at high altitudes. Other sources of nitro-
gen  oxides originating from the earth's surface were also
considered.   These concerns gradually diminished, because
the  quantities of nitrogen  oxides likely to  be involved
were insufficient to cause a serious threat to  the  ozone
layer.   However,  concern  over halogen  pollution of the
upper  atmosphere  arose  during  the  mid-1970s  (section
4.2.3).   The halogens of immediate  concern were chlorine
and bromine. The main source for chlorine is chlorofluoro-
carbons, which are released worldwide from such sources as
aerosol  spray cans, certain plastic foams, refrigerators,
and refrigerative air conditioners.

    Many gases emitted as a result of industrial and agri-
cultural  activities can accumulate in  the Earth's atmos-
phere and ultimately contribute to alterations in the ver-
tical  distribution  and  concentrations of  stratospheric
ozone. Among the most important are those trace gases that
have  long residence times in the atmosphere.  This allows
accumulation  in  the  troposphere and  a  gradual  upward
migration  of the gases  into the stratosphere  where they
contribute to depletion of stratospheric ozone. The atmos-
pheric  and  chemical  processes  involved  are  extremely
complex (US EPA, 1987a). Trace gases of particular concern
include  certain  long-lived chlorofluorocarbons,  such as
CFC-11,  CFC-12,  and  CFC-113 (for  atmospheric residence
times see section 4.3). Since the transport of these gases
to the stratosphere is slow, their residence  times  there
are long, and the removal processes are slow,  any  effect
on stratospheric ozone already seen is probably the result
of  anthropogenic emissions of these gases several decades
ago.   Those gases already in the atmosphere will continue
to  exert stratospheric ozone depletion  effects well into
the next century.

    The  atmospheric  models  that  predict  future  ozone
depletion  are in a continual process of refinement.  Over
the years, predicted decreases in stratospheric ozone have
ranged from 4 to 18%, based on the  stratospheric  concen-
trations of chlorine expected from the 1974 levels of CFC-
11 and CFC-12 emissions.  However, it has  gradually  been
realized  that other gases will influence column ozone and
that  the size and  direction of the  predicted change  in
total ozone during the next century depend  critically  on
the  assumption of the multiple trace-gas scenarios.  Many
of  the  modelling  scenarios tended  to assume relatively
uniform  rates of ozone layer reduction widely distributed

above  all regions of the  Earth.  However, areas of  dis-
tinctly  greater  depletion (ranging  from  15 to  40%  in
recent  years) have been  identified over the  South Polar
region  during September to  November of each  year.   The
evidence  suggests  a  likely gradual  expansion  of  this
"Antarctic  Ozone Hole" ultimately to  extend beyond the
South  Polar region, possibly  coming to reach  over  more
heavily  populated areas of the Southern Hemisphere. Simi-
larly, it is considered likely that an  analogous,  though
less  intense, zone of  upper level ozone  reduction  will
occur  over the North Polar  region and expand over  popu-
lated areas of the Northern Hemisphere.

    Although  ozone constitutes a very small proportion of
the stratosphere, it plays a major role in protecting life
on this planet.  The result of changes in the  density  of
the  total ozone column could, therefore, be far-reaching.
The  natural distribution of  ozone in the  Earth's atmos-
phere, concentrated most heavily in a diffuse layer in the
stratosphere,  is  crucial  in helping  to  protect  human
beings,  other biological systems, and  man-made materials
from  the harmful effects  of certain wavelengths  of sun-
light.   Stratospheric ozone exerts its beneficial effects
by  absorbing ultraviolet radiation in  the 200- to 320-nm
range,  allowing  only  reduced amounts  of UV-B radiation
(280- to  320-nm  waveband)  to penetrate  to  the Earth's
surface. In addition, the vertical distribution of strato-
spheric  ozone and  relative dryness  of the  air  in  the
stratosphere help to maintain the radiative balance of the
Earth.   Depletion of the  stratospheric ozone layer  can,
therefore,  be  expected to  lead  to damaging  effects on
human health and the environment (i) directly by increased
penetration of UV-B radiation to the Earth's  surface  and
(ii)  indirectly through the  influence of changes  in the
vertical  distribution  of  stratospheric ozone  and water
vapour  that  contribute  to global  warming  effects  and
altered climatic conditions.  The possibility of increased
exposure to solar UV-B radiation is a particular cause for
concern  because of its  effect on humans,  other animals,
plants,  certain manufactured materials, and photochemical
smog  production.  Most of the known biological effects of
UV-B  radiation  are  damaging.  Detailed  discussions  of
evolving  concern about stratospheric ozone  depletion and
assessment  of the scientific base underlying such concern
can  be found in several recent national and international
expert  work  group reports  or  symposia (e.g.,  US  EPA,
1987a; Schneider et al., 1989; WMO/Canada DOE, 1989).  The
following  sections summarize key points from such sources
and  discuss  their  implications for  the  development of
effective  international efforts to cope  with ozone layer

6.2.  Terrestrial plants

    Increased  UV-B irradiation of the Earth's surface due
to ozone layer depletion can be expected to have  a  nega-
tive  impact on both terrestrial and aquatic biota. In as-
sessing the impact of increased exposure to UV-B radiation
for  crops and terrestrial  ecosystems, it must  be recog-
nized that existing knowledge is in many  ways  deficient.
The effects of enhanced levels of UV-B radiation have been
studied  in only a few representative species from some of
the major terrestrial ecosystems.  Most knowledge has been
derived  from studies that focused upon agricultural crops
and were conducted at mid-latitudes. Despite uncertainties
resulting  from the complexities of field experiments, the
available  data suggest that crop yields are vulnerable to
increased  levels of solar UV-B radiation.  Unlike drought
or  other geographically isolated  stresses, stratospheric
ozone  depletion  would affect  all  areas of  the  world,
including  ecosystems whose UV-B sensitivity  has not been

    Out  of more than  200 species and cultivars  screened
for UV tolerance, about two-thirds have been found  to  be
sensitive. Most tests were done in controlled environments
with  UV radiation from artificial sources.  The UV sensi-
tivity  was usually exaggerated  when compared to  results
obtained by exposure to solar radiation in the field.  The
most  sensitive plant groups include crops related to peas
and  beans, melons, mustard,  and cabbage, but  there  are
large differences in sensitivity between the various crops
studied in the field (US EPA, 1987b). In general, UV radi-
ation causes reduced leaf and stem growth, lower total dry
weight,  and  lower  photosynthetic activity  in sensitive
cultivars  (Tevini & Iwanzik,  1986).  These results  were
corroborated in an experiment simulating a 25% enhancement
of   solar  UV-B  radiation   (equivalent  to  12%   ozone
reduction), where UV-B exposure was controlled by an arti-
ficial ozone filter at a high altitude and at  a  southern
latitude  (Tevini  et al.,  1986).   Members of  the grass
family  were generally less  sensitive (with some  notable
exceptions),  possibly due to protective abilities such as
photorepair  or production of screening pigments (Beggs et
al., 1986).

    The  large variation in sensitivity  that exists among
cultivars  within  each  crop species  suggests  that some
degree  of UV tolerance  must be present  in the  existing
gene  pool. The genetic basis for differences in UV-B sen-
sitivity  is not fully understood. However, it is possible
that selective crop breeding might help mitigate  some  of
the potentially deleterious effects (Teramura, 1983).

    In  addition  to other  factors,  the quality  of crop
yield  may be reduced  by increased levels  of UV-B  radi-
ation.  Changes in crop quality have not been specifically

examined  in many studies,  but reduced quality  has  been
noted  in certain cultivars of tomato, potato, sugar beet,
and  soybean.   The protein  and  oil content  of specific
cultivars  of soybean seeds were reduced by up to 10% when
plants were exposed to UV levels equivalent to a 25% ozone
depletion (US EPA, 1987b).

    Increased  levels  of  UV-B radiation  may also affect
forest  productivity.  Only limited data  are available on
coniferous  species, but in studies by Sullivan & Teramura
(1988)  about one-half of  the species of  seedlings  were
adversely  affected by UV-B  radiation.  In loblolly  pine
seedlings, growth and photosynthesis were reduced in field
studies  simulating  a  40% ozone  reduction  (Teramura  &
Sullivan,  1988).  However, extrapolation from the results
of  seedling studies to  forested ecosystems is  not poss-
ible,  nor is interpolation  of predicted results  at  ex-
posure levels simulating a lower level of ozone reduction.

    The  existing  data  also suggest  that increased UV-B
radiation  will modify the  distribution and abundance  of
plants,  and potentially change  ecosystem structure as  a
result of an alteration of the competitive balance between
different  species. Even small changes in competitive bal-
ance  over a period of time can result in large changes in
community  structure  and  composition (Gold  &  Caldwell,
1983).   The  shift in  competitive  balance may  occur in
response  to subtle changes in plant growth, without large
changes  in  fundamental  physiological processes  such as
photosynthesis  (Beyschlag et al., 1988).   The alteration
of the competitive balance of species is a dynamic process
affected  by  the  competing species  and  their immediate
environment.   Unfortunately, neither a quantitative nor a
qualitative  prediction of how  these ecosystems might  be
altered  can  be  determined from  the  current  knowledge

6.3.  Aquatic organisms

    Various  experiments have demonstrated that UV-B radi-
ation causes damage to fish larvae and  juveniles,  shrimp
larvae, crab larvae, copepods, and plants essential to the
marine food web.  These damaging effects include decreased
fecundity,  growth, survival, and other  reduced functions
in  these organisms (Worrest,  1982; US EPA,  1987c). Evi-
dence   indicates  that  ambient  solar   UV-B  radiation,
although not nearly as important as light, temperature, or
nutrient  levels, is currently an  important limiting eco-
logical  factor,  and that  even  small increases  in UV-B
exposure  could  result  in significant  ecosystem changes
(Damkaer, 1982).

    Effects  induced  by  solar UV-B  radiation  have been
measured to a depth of more than 20 metres in clear waters
and  more  than  five metres  in  less  clear water.   The

euphotic  zone (i.e. water depth with levels of light suf-
ficient  for  positive  net photosynthesis)  is frequently
taken as the water column that reaches down to  the  depth
at which photosynthetically active radiation is reduced by
99%.   In  marine  ecosystems, UV-B  radiation  penetrates
approximately  the upper 10%  of the marine  euphotic zone
before  it is reduced  by 99% of  its surface  irradiance.
Penetration of UV-B radiation into natural waters is a key
variable in assessing the potential impact of  this  radi-
ation on any aquatic ecosystem (US EPA, 1987c).

    In marine plant communities a change in species compo-
sition rather than a decrease in net production  would  be
the  probable result of increased  UV-B exposure (Worrest,
1983).  A change in community composition at the  base  of
food webs may produce instabilities within ecosystems that
could  affect  higher  trophic levels  (Kelly, 1986).  The
generation time of marine phytoplankton is in the range of
hours to days, whereas the potential increase  in  ambient
levels of solar UV-B irradiance will occur  over  decades.
The  question remains as to  whether the gene pool  within
species  is  capable  of adapting  during  this relatively
gradual  (relative to the  generation time of  the  target
organisms) change in exposure to UV-B radiation.  There is
evidence that a decrease in column ozone  abundance  could
diminish the near-surface season of invertebrate zooplank-
ton  populations.  For some zooplankton, the time spent at
or  near the surface  is critical for  food gathering  and
breeding.  Whether these populations  could endure a  sig-
nificant  shortening  of  the surface  season  is  unknown
(Damkaer et al., 1980).

    The  direct effect of  UV-B radiation on  edible  fish
larvae   closely  parallels  the  effect  on  invertebrate
zooplankton.   More  information  is required  on seasonal
abundances and vertical distributions of fish larvae, ver-
tical  mixing,  and  penetration of  UV-B  radiation  into
appropriate  water columns before  effects of exposure  to
solar  UV-B radiation can  be predicted.  However,  in one
study involving anchovy larvae, it was calculated  that  a
20% increase in UV-B radiation (which would accompany a 9%
depletion of total column ozone) would result in the death
of  about 8% of  the annual larval  population (Hunter  et
al., 1982).  This one study was performed in  the  labora-
tory,  and even the  control animals had  significant mor-
tality  at the end of the normal larval period. This high-
lights  the need for  caution when trying  to  extrapolate
conclusions  to natural conditions when  those conclusions
are based on results from laboratory studies.

    In  many countries marine species supply more than 50%
of the dietary protein, and in developing  countries  this
percentage is often higher.  Research is needed to improve
our  understanding  of  how stratospheric  ozone depletion

could influence the world food supply.  However, effective
steps  to  minimize  stratospheric zone  depletion  cannot
await the outcome of such research.

6.4.  Research needs

    Future  work  concerning  UV-B effects  on terrestrial
ecosystems  must  proceed  on a  broad front.  Sensitivity
screenings   and  dose-response  studies  must  expand  to
include  representative species from a wider range of eco-
system  types and a wider range of plant types within eco-
systems  of particular interest. Knowledge of species sen-
sitivities  and their geographic  ranges can then  be com-
bined  with information on current and projected levels of
UV-B in order to identify areas of greatest  concern.   An
understanding  of how sensitivity  to UV-B is  affected by
other  environmental  factors  will aid  in  this process.
Additional  work  at the  biochemical  level is  needed to
clarify  interactions of UV-B  radiation and plant  metab-
olism as well as the nature of effects of  UV-B  radiation
on pests and pathogens.

    Ultimately, the information gathered in field and lab-
oratory  studies must be put into the context of ecosystem
properties,   including  primary  productivity,   nutrient
cycling,  resistance to disturbance,  and the capacity  to
recover  from disturbance.  Efforts are  clearly needed to
integrate what is known about the influences  of  elevated
UV-B irradiance on plants with what is known  about  plant
stress  associated with other human-induced changes in the

    In  order to quantify the effects on marine systems of
UV-B radiation on an ocean-wide basis, there is a need for
additional  data on the penetration of UV-B radiation as a
function of water mass, concentration of particulates, and
presence  of plankton.  These  data must be  combined with
accurate  measurements of total  incident radiation, as  a
function  of angle  of incidence  and time,  to arrive  at
reliable estimates of both total UV-B radiation  dose  and
dose rate.

    There  is a clear  need to measure  fish-larval sensi-
tivity to UV-B radiation for many resource species, refine
the  links between exposure  of primary producers  to UV-B
radiation  and effects on fish, assess the impact of food-
web  changes on fish  yield, and delineate  the mitigating
mechanisms available to the organism.

    Studies on changes in population size and diversity as
a  result of stress would provide insights for predictions
of  the effects of  UV-B increases in  a given  ecological
niche (Worrest et al., 1978, 1981a,b; Worrest, 1983). Data
describing  changes  resulting from  environmental stress,
such as contamination from toxic substances or temperature

change, could be combined with data on the  efficiency  of
energy conversion between trophic levels, upon which a re-
source species relies, to estimate the potential reduction
in fish catch.  To narrow the reliability limits  of  such
predictions,  field investigations into the  resiliency of
affected populations are required.

    There  is a paucity  of information on  the impact  of
UV-B radiation on marine resource species. The  fact  that
dose-response  sensitivity  data  exist  for  only  a  few
species greatly impedes our ability to extrapolate  to  an
overall assessment of the risk to marine fisheries.  It is
important  to  be  able to  translate  known intracellular
cause-and-effect  relationships of UV damage to effects on
simple   or  single-celled  organisms  and  to  population

    Knowledge  of  adaptive  or protective  mechanisms  by
which  marine organisms minimize the  effects of increased
UV-B radiation in the ocean's surface layers  is  lacking.
No  avoidance mechanisms specific  to UV-B radiation  have
been  described  for marine  organisms, although avoidance
mechanisms to visible light may lessen the impact  of  the
concurrent  UV radiation. While pigmentation occurs exten-
sively  in marine organisms, the  degree to which it  con-
tributes to UV-B protection is unknown.

    The  time scale of  adaptation or repair,  compared to
the  time scale of increased UV-B radiation, is an import-
ant  factor.  Are genetic mechanisms sufficient to obviate
the  negative impacts?  Do they  affect competitor species
over similar time scales?  What organisms are pre-disposed
to  environmental (i.e. non-genetic) protective behaviour?
These questions must be addressed as part of the framework
of risk assessment.


7.1.  Absorption

    Chlorofluorocarbon  propellants and solvents  may pre-
sent a hazard for human beings by  inhalation,  ingestion,
and  dermal absorption.  However, because  of the physical
properties  and uses of these compounds, inhalation is the
most  common route of  entry, and exhalation  is the  most
significant route of elimination.

    Information  concerning  chlorofluorocarbon absorption
has been obtained in two types of studies:

*   chlorofluorocarbon retention in the lungs;
*   chlorofluorocarbon blood levels after inhalation.

    The  relative amounts of CFC-11,  CFC-12, CFC-113, and
CFC-114  absorbed by human  beings have been  measured  in
breath-holding   studies (Paulet & Chevrier,  1969; Morgan
et  al.,  1972).   Retention was  measured using radioiso-
topically  marked  chlorofluorocarbons by  subtracting the
radioactivity  exhaled  30 min  after inhalation  from the
amount  of radioactivity inhaled with a single breath.  In
terms  of  absorption  the following  order  was obtained:
CFC-11 ~ CFC-113 > CFC-114 ~ CFC-12,     with  retentions
of 23%, 19.8%, 12.2%, and 10.3%, respectively.  Shargel  &
Koss  (1972) exposed dogs  to an equal  weight mixture  of
CFC-11, CFC-12, CFC-113, and CFC-114, and obtained similar

    In  other studies, human volunteers (Aviado & Micozzi,
1981)  and dogs (Azar et al., 1973) were exposed to CFC-11
at  a  concentration  of 5710 mg/m3 (1000 ppm)   and for a
period of 8 h or 10 min, respectively. The blood levels in
the  human volunteers were  4.69 µg/ml   and in  the  dogs
6.5-10 µg/ml.  According to a mathematical model developed
for  the description of  the pharmacokinetics, 77%  of the
dose applied was absorbed.

    Azar  et al. (1973) determined  the corresponding data
for  CFC-12 in  beagle dogs.   After an  exposure to  5030
mg/m3   (1000 ppm) for a period of 10 min, 1.1 µg/ml   was
found  in the arterial blood and 0.4 µg/ml   in the venous
system.  At higher concentrations, the arterial and venous
concentrations  were similar.  Trochimowicz et  al. (1974)
found,  under  similar  conditions (1000 ppm,  1 min inha-
lation period), that the blood level in dogs  for  CFC-113
was 2.7 µg/ml  (arterial) and 1.9 µg/ml  (venous), and for
CFC-114 0.4 µg/ml and 0.2 µg/ml, respectively.

    In  a study by Angerer et al. (1985), three volunteers
were  exposed to a CFC-11 concentration of  3750 mg/m3 (657
ppm).  The average value of pulmonary retention was 18.9%.
CFC-11 levels in alveolar air and blood  were    3066 mg/m3
(537 ppm) and 2.8 µg/ml, respectively.

    Further  absorption  and elimination  data from CFC-11
and  CFC-12 atomizer administrations indicated that, while
CFC-11  is  more  readily absorbed  by  mammals (including
humans) than CFC-12, the degree of preferential absorption
may  vary among individuals (Dollery et al., 1970; Allen &
Hanburys Ltd, 1971; Paterson et al., 1971; Shargel & Koss,
1972).   Similar  information on  the different absorption
rates  has been obtained from other studies. Chlorofluoro-
carbons  were administered to dogs for 5 min at fixed con-
centrations  between 0.3 and 10 vol % in the inspired air.
The  blood  concentrations  determined up  to 60 min after
exposure  indicated that CFC-11  is more readily  absorbed
than CFC-12 or CFC-114 (Clark & Tinston, 1972a).

    The  results of Adir et al. (1975) and Brugnone et al.
(1984) provide additional evidence that CFC-11 is absorbed
to  a greater extent than CFC-12 in dogs and rabbits.  The
absorption  data correlate well  with the liquid/gas  par-
tition  coefficients for these  compounds in whole  blood,
serum, and olive oil shown in Table 11.

    CFC-12  was absorbed 4 times more readily than CFC-114
in a study by Rauws et al. (1973) in which rats  were  ex-
posed  to a mixture of CFC-11, CFC-12, and CFC-114 (weight
ratio  of 1:2:1).   A similar  pattern was  also  seen  in
monkeys  by Taylor et al.  (1971).  In each instance,  the
ratio  of CFC-12 to CFC-114  in arterial blood was  higher
than the ratio of exposure concentrations, indicating that
CFC-12 was slightly more readily absorbed than CFC-114.

    The  available data on chlorofluorocarbon uptake indi-
cate  that chlorofluorocarbons can be  absorbed across the
alveolar  membrane, gastro-intestinal tract, the skin, and
internal  organs.  Following inhalation, they are absorbed
rapidly by the blood.  Blood-tissue absorption is probably
the  rate-limiting  step.   After an  initial, rapid blood
level  stabilization,  chlorofluorocarbons  are still  ab-
sorbed by body tissues and continue to enter the body.

Table 11.  Partition coefficients of various chlorofluorocarbons
Compound  Whole blooda  Whole bloodb  Serumc   Olive 
          (rat)         (human)       (human)  oilc
CFC-11    1.4           0.87           0.9     27
CFC-12    0.2           0.15           0.2     3
CFC-113                                0.8     32
CFC-114                 0.15           0.2     5
a   From: Allen & Hanburys, Ltd (1971).
b   From: Chiou & Niazi (1973).
c   From: Morgan et al. (1972).

7.2.  Distribution

    Allen  & Hanburys, Ltd. (1971) found in mice that both
CFC-11  and CFC-12 are taken up by heart, fat, and adrenal
tissue after 5-min inhalation exposures. CFC-11 is concen-
trated  from  the  blood to  the  greatest  extent in  the
adrenals  followed by the fat, then the heart.  A similar,
though  less pronounced, pattern is evident for CFC-12 but
CFC-11 is absorbed and concentrated in all of  these  tis-
sues to a much greater extent than CFC-12. Paulet  et  al.
(1975) noted that both CFC-11 and CFC-12  are  distributed
to  the  cerebrospinal  fluid  of  dogs  after  inhalation

    Following   inhalation  exposures  lasting  7-14 days,
Carter  (1970) noted distribution patterns  for CFC-113 in
rats  that were qualitatively  similar to those  noted for
CFC-11 and CFC-12 by Allen & Hanburys, Ltd.  (1971).   The
major  difference from the  CFC-11 and CFC-12  results was
that almost all of the CFC-113 concentration  occurred  in
the fat, while adrenal levels were relatively low and even
decreased  as exposure continued (it  should be emphasized
that  the exposures  to CFC-11  and CFC-12  were for  only
5 min).  The other organ  levels did not  change  signifi-
cantly  from a 7-day to  a 14-day exposure, which  is con-
sistent  with  the  idea  that  such  concentrations  will
stabilize as equilibria between ambient air concentration,
blood level, and tissue levels are reached.  In  rats  and
guinea-pigs,  shortly  after  exposure to  CFC-113, Furuya
(1979)   noted   the  following   tissue  distribution  in
decreasing  order: fat, brain, liver, kidney, heart, lung,
muscle, and blood.

    In  summary, chlorofluorocarbons are  rapidly absorbed
after inhalation and are distributed by blood into practi-
cally  all  tissues.   Relatively high  concentrations are
found in fat, but also in organs with good blood supply.

7.3.  Metabolic transformation

    Of the nine chlorofluorocarbons reviewed in this docu-
ment,  some data regarding metabolism exists only for CFC-
11, CFC-12, CFC-112a, and CFC-113a.

    Cox  et  al. (1972a)  found  no evidence  of reductive
dehalogenation  of CFC-11 in microsomal  preparations from
rats,  chickens, or other species.  However, the reductive
dechlorination  in  vitro of CFC-11 to HCFC-21 by rat liver
microsomes  was reported by  Wolf et al.  (1978).  In vitro
metabolism   studies suggested that CFC-112a  and CFC-113a
can  be metabolized by  reductive dechlorination and  that
the  reaction is catalyzed  by cytochrome P-450  from  rat
liver  microsomes.   However,  no  metabolites  of  either
compound  were  identified  (Salmon et  al.,  1981,  1985;
Nastainczyk et al., 1982a,b).

    Published studies on  in vivo  metabolism exist only for
CFC-11  and CFC-12.  Eddy  & Griffith (1971)  administered
14C-labelled    CFC-12  to  rats  by  the  oral  route and
reported  a small amount of  metabolism.  About 2% of  the
total dose was exhaled as 14CO2 and   0.5% was excreted in
urine.   CFC-12  and/or  its metabolites  were  no  longer
detectable in the body 30 h after administration.

    Blake  & Mergner (1974)  exposed beagle dogs  for 6-20
min to CFC-11 (5710 to 28 550 mg/m3;   1000  to  5000 ppm,
v/v) or CFC-12 (40 240 to 60 380 mg/m3;   8000  to  12 000
ppm,  v/v) containing up to  180 µCi  of  14C-chlorofluoro-
carbon.  Virtually all the administered chlorofluorocarbon
was recovered in exhaled air within one hour  with  either
material. Only traces of radioactivity were found in urine
or  exhaled  CO2    and may  have  represented unavoidable
radiolabelled  impurities  rather  than metabolites.   The
authors  concluded that less than  1% of either CFC-11  or
CFC-12  is  metabolized  after inhalation.   The preceding
results  were essentially confirmed in human volunteers by
the  same  authors  (Mergner et  al., 1975). Radiolabelled
CFC-11 (571 mg/m3;   100 ppm) and CFC-12 (503 mg/m3;   100
ppm) were given by inhalation to one male and  one  female
volunteer for 7-17 min.  As was the case in  dogs,  little
or  no biotransformation of either  chlorofluorocarbon was
observed.   Total metabolites were equal to, or less than,
0.2% of the administered dose.

    The results of the preceding studies suggest that CFC-
11 and CFC-12 are metabolized to a very small  extent,  if
at all, in mammals following brief inhalation exposures.

7.4.  Elimination and excretion in expired air, faeces, and urine

    Regardless  of the route of entry, chlorofluorocarbons
appear  to  be  eliminated almost  exclusively through the
repiratory  tract.  Little, if any,  chlorofluorocarbon or
metabolite  has  ever been  reported  in urine  or  faeces
(Matsumoto et al., 1963; Blake & Mergner, 1974; Mergner et
al., 1975).

7.5.  Retention and turnover

    When exposure is terminated, the more readily absorbed
compounds are retained longer. The retention of chloroflu-
orocarbons  after inhalation follows the same order as the
amount absorbed during exposure:

         CFC-11 ~ CFC-113 > CFC-114 ~ CFC-12

    In  human  studies  designed  to  mimic  exposures  to
chlorofluorocarbons  from  atomizers,  the  initial  blood
half-lives  for CFC-11 were in  the range of 6 seconds  to
1 min (Paterson et al., 1971).

    In  one study, volunteers  exposed to CFC-11  at  3751
mg/m3 (657 ppm)  for 150-210 min showed half-lives for the
initial and second phases of elimination from venous blood
of  11 min and 1 h,  respectively (Angerer et  al., 1985).
Half-lives  for the initial  and second phases  of  CFC-11
elimination in alveolar air were 7 min and 1.8 h, respect-
ively (Angerer et al., 1985).  Average pulmonary retention
at  an apparent  steady state  after 1 h  of exposure  was
18.2%.   Similarly,  the data  of  Brugnone et  al. (1984)
indicate a pulmonary retention of 19% for CFC-11  and  18%
for CFC-12 in workers during occupational exposure.

    Studies in which dogs were administered CFC-11 or CFC-
12  by intravenous infusion indicated that the elimination
of  CFC-11  and CFC-12  from  venous blood  was  triphasic
(Niazi  & Chiou, 1975,  1977).  A 3-compartment  model was
proposed  with  initial, intermediate,  and terminal half-
lives  of 3.2, 16, and  93 min for CFC-11 and  1.47, 7.95,
and  58.50 min for CFC-12.  Adir et al. (1975) also fitted
their  venous  blood  elimination data  to a 3-compartment
model.  Estimates of half-lives for the terminal phases of
CFC-11 elimination were 6.30 and 24.75 min for  two  human
volunteers  and 13.86-21 min (mean, 18.34)  for four dogs.
For the terminal phases of CFC-12 elimination,  the  half-
lives were 9.63 min for one human volunteer and 8.45-11.35
min (mean, 9.90) for three dogs.

    In  dogs exposed to  CFC-11 by atomizers,  the initial
and  terminal half-lives in venous  blood were at 0.6  and
4.03 min, respectively (McClure, 1972). The terminal half-
life of 80 min in dogs after exposures to  ambient  CFC-11
concentrations  of 2, 5, and  7.5% (Amin et al.,  1979) is
close to the terminal half-lives reported by Niazi & Chiou

    Reinhardt  et al. (1971a) conducted  retention studies
on  CFC-113 in human  volunteers over occupationally  rel-
evant  periods.  They measured the chlorofluorocarbon con-
centration  in the expired  air of volunteers  exposed  to
3835 mg/m3   (0.05%) or 7670 mg/m3   (0.1%) for 3 h in the
morning and 3 h in the afternoon.  Although there  was  no
indication  of chlorofluorocarbon accumulation, detectable
levels  were  retained overnight  in  four cases  at  3835
mg/m3    and in 14 cases at 7670 mg/m3.   In one instance,
there was a detectable level on a Monday morning following
a  final exposure to  7670 mg/m3   (0.1%) on  the previous

7.6.  Reaction with body components

    Lessard  & Paulet (1985) concluded that simple dissol-
ution of CFC-12 in the lipid layer of biological membranes
with  ensuing  alteration  of membrane  configuration  may
account for its anaesthetic effect and some of its cardiac

effects.   Young & Parker (1972),  however, suggested that
CFC-12  is bound to the hydrophilic areas of various phos-
pholipids and that potassium chloride may stop adrenaline-
induced  arrhythmia in hearts sensitized by CFC-12 by dis-
placing the CFC-12 molecule held by the phospholipid.

    CFC-11 has been shown to bind  in vitro to liver micro-
somal protein and lipid (Uehleke et al., 1977; Cox et al.,
1972a,b)  and to cytochrome  P-450 (Cox et  al.,  1972a,b;
Wolf  et al., 1977, 1978). Vainio et al., (1980) also dem-
onstrated binding of CFC-113 to cytochrome P-450.  In view
of  the very low  liver toxicity potential  of CFC-11  and
CFC-113,  the  toxicological  significance  of  the  P-450
binding is unknown.


8.1.  Single exposures

8.1.1.  Acute inhalation toxicity

    A  number of chlorofluoromethanes and chlorofluoroeth-
anes  have been tested  for acute inhalation  toxicity  in
laboratory animals.  Because most of the information is of
limited  importance for a quantitative risk assessment, it
will not be discussed in detail.  The data  are  presented
in Table 12.

    Of  the fully halogenated chlorofluoromethanes, CFC-12
and  CFC-13 show extremely low  acute inhalation toxicity.
CFC-11  also  has  low acute  inhalation  toxicity, lethal
concentrations   being  in  the  range   of    571-1427 g/m3
(100 000-250 000 ppm).

    Within  the chlorofluoroethanes, CFC-114 and  115 seem
to be of an extremely low acute toxicity, followed by CFC-
113 and CFC-112.

    The symptomatology of acute intoxication is character-
ized  by  central  nervous system  effects  and  secondary
effects on the cardiovascular and respiratory systems.

8.1.2.  Acute oral toxicity

    Very little information is available on the acute oral
toxicity  of chlorofluorocarbons.  The lethality  data for
some chlorofluorocarbons are summarized in Table 13.  With
the exception of a slight increase in liver weight follow-
ing exposure to CFC-112 and CFC-112a at  25 000 mg/kg,  no
gross  or histological abnormalities were noted by Clayton

8.2.  Short-term exposures

    In this monograph, short-term exposures are defined as
those  involving repeated daily exposure up to 90 days and
long-term studies as those longer than 90 days (see 8.4).

Table 12.  Acute inhalation toxicity of fully halogenated chlorofluorocarbons
Compound    Conc.a   Conc.b     Exposure  Effects observed    Reference
and                             period
species                         (min)

Guinea-pig  22-25    125-143    120       tremor, dyspnoea    Nuckolls (1933)
            45-51    257-291    120       tremor, incipient
            100      571        50        deep narcosis       Scholz (1961)
            250      1427       30        death (LC50)        Caujolle (1964)
                                                              Paulet (1969)

Mouse       10       57         1440      no clinical signs   Quevauviller et al. (1963)
            100      571        30        death (LC50)        Paulet (1969)

Rat         50       285        120       incipient narcosis  Scholz (1961)
            90       514        30        deep narcosis       Lester & Greenberg (1950)
            150      856        30        death (LC50)        Paulet (1969)

Hamster     100      571        240       death (LC50)        Taylor & Drew (1974)

Cat         100      571        60        death               Scholz (1961)


Guinea-pig  540      2716       30        initial effect on   Paulet (1969)
            900      4527       30        CNS narcosis, but  
                                          no mortalities

Mouse       320      1610       30        initial effect      Paulet (1969)
                                          on CNS

Rat         200      1006       30        no effect           Lester & Greenberg (1950)
            300-400  1509-2012  30        tremor
            500      2515       30        reduced reflexes
            700-800  3521-4024  30        deep narcosis, no
            800      4024       360       no mortality

Monkey,     200      1006       420-480   incoordination      Sayers et al. (1930)


Guinea-pig  600      2604       120       no effect           Weigand (1971)

Rat         600      2604       120       no effect           Weigand (1971)

Table 12 (contd.)
Compound    Conc.a   Conc.b     Exposure  Effects observed    Reference
and                             period
species                         (min)


Rat         30       254        40-60     lethal (pulmonary   Greenberg & Lester (1950)
            5-10     42-85      1080      lethal (pulmonary


Guinea-pig  120      935        60        mortality (LC50)    Trockimowitz (1984)

Mouse       90-95    701-740    120       death (LC50)        Desoille et al. (1968)
            90       701        120       death (LC50)        Trockimowitz (1984)

Rat         52.5     409        240       death (LC50)        Trockimowitz (1984)
            110      857        120       death (LC50)

Rabbit      59.5     463        120       death (LC50)        Trockimowitz (1984)

Guinea-pig  20-47    142-334    120       dyspnoea            Nuckolls (1933)
            400      2844       1440      incoordination      Scholz (1961)

Mouse       700      4977       30        no mortality        Paulet (1969)

Rat         300      2133       120       incoordination      Scholz (1961)
            600      4266       120       deep narcosis
            720      5119       30        no mortality        Paulet (1969)

Rabbit      750      5332       30        no mortality        Paulet (1969)


Guinea-pig  600      3852       120       no effect           Weigand (1971)
Rat         600      3852       120       no effect           Weigand (1971)
a  Concentration in parts per thousand.
b  Concentration in g/m3.
8.2.1.  Inhalation exposure

    The  results of short-term inhalation studies are sum-
marized in Table 14.

    In  the case of  CFC-11, intermittent exposure  to 143
g/m3    (25 000 ppm) (3.5 h/day, 5 days/week  for 4 weeks)
did  not result in any adverse effects in rats and guinea-
pigs  (Scholz,  1962).   Similarly,  no  treatment-related
effects  occurred in rats,  guinea-pigs, monkeys, or  dogs
after  intermittent  exposure to  58.5 g/m3   (10 250 ppm)
(8 h/day,  5 days/week for 6 weeks) or continuous exposure
to  57.1 g/m3   (10 000 ppm) for 90 days  (Jenkins et al.,
1970).   Leuschner et al. (1983) exposed groups of dogs to
28.5 g/m3 (5000 ppm)  and rats to 57.1 g/m3   (10 000 ppm)
for 6 h/day during 90 days and did not find any treatment-
related changes. The lowest reported effect level for CFC-
11  was 68.5 g/m3   (12 000 ppm), above which pathological
changes in the brain, liver, lung, and spleen of  all  the
rats were observed (Clayton, 1966).

Table 13.  Acute oral toxicity of various chlorofluoroalkanes 
to ratsa
Compound         Approximate lethal dose (mg/kg)
CFC-11           3725b
CFC-12           >1000c
CFC-112          25 000
CFC-112a         25 000
CFC-113          45 000d
CFC-114          >2250c
a  Modified from: Clayton (1966).
b  From: Slater (1965).
c  Maximum feasible dose of chlorofluorocarbon 
   dissolved in peanut oil.
d  LD50 = 43 000 mg/kg.

    The exposure of rats, cats, guinea-pigs, and  dogs  to
CFC-12  at 503 g/m3 (100 000 ppm)  (3.5 h/day, 5 days/week
for  4 weeks)  caused  no adverse  effects (Scholz, 1962).
Fatty  infiltration and necrosis in the liver was observed
by  Prendergast  et  al. (1967)  after continuous (90-day)
exposure of guinea-pigs to CFC-12 at 4.02 g/m3   (800 ppm)
but  not in rats, rabbits, dogs, or monkeys exposed to the
same  dose  regimen.   Exposure  to  CFC-12  for   90 days
(6 h/day)  of dogs at  25.1 g/m3   (5000 ppm) and  rats at
50.3 g/m3    (10 000 ppm)  was  without any  toxic  effect
(Leuschner et al., 1983).

    In most inhalation toxicity studies, CFC-113 caused no
adverse effects, even after a 90-day exposure of  rats  to
155 g/m3    (20 000 ppm) (Trochimowicz, 1984) and  dogs to
40 g/m3    (5000 ppm) (Leuschner et al.,  1983).  However,
Clayton (1966) reported effects in rats after 30 exposures
(each  of 7 h) to 40 g/m3    (5000 ppm) and Vainio et  al.
(1980) found changes in liver enzyme activities  and  pro-
liferation  of  the  smooth  endoplasmic  reticulum  after
exposure  of  rats  to  15.6-31.2 g/m3     (2000-4000 ppm)

(6 h/day for 7-14 days).  Enlarged thyroids in monkeys and
increased  kidney  weights  in rats  were  described after
continuous  exposure to 15.6 g/m3   (2000 ppm) for 14 days
(Carter  et al., 1970), but these effects were minimal and
could not be reproduced under the same exposure conditions
(Trochimowicz, 1984).

    CFC-114  caused no effects in mice, rats, guinea-pigs,
cats,  or  dogs  after intermittent  exposure  to  concen-
trations  as high as  711 g/m3   (100 000 ppm).  At higher
dose  levels (995-1422 g/m3;   140 000-200 000 ppm)  signs
of intoxication were noted in guinea-pigs, dogs, rats, and
mice  (see  Table 13).  Rats  exposed  to CFC-112  at 8470
mg/m3    (1000 ppm) (6 h/day for 31 days) developed slight
liver  changes.  Exposure to the same concentration for 18
h/day  during 16 days caused no toxic effects, whereas CNS
and  respiratory  signs occurred  at higher concentrations
(25 410 mg/m3;    3000 ppm) (Clayton, 1967).  In contrast,
CFC-115  at 642 g/m3 (100 000 ppm)  was tolerated by rats,
mice,  rabbits, and dogs for 90 days (6 h/day) without any
toxic effect (Clayton, 1966).

    In  summary, it can be concluded that short-term inha-
lation toxicity is low. Toxic effects relate mainly to the
central  nervous  system,  the respiratory  tract, and the

Table 14.  Short-term inhalation exposures of various animals to chlorofluorocarbons
Species and      Exposure                          Effects                          Reference
number of        g/m3a

Rat (4)          68 (12 000), 4 h/day, 10 days     pathological changes in lung,    Clayton (1966)
                                                   liver, brain, and spleen
Rat (5)          143 (25 000), 3.5 h/day,          no adverse effects               Scholz (1962)
                 5 days/week, 4 weeks
Dog (2)          71 (12 500 ppm, 3.5 h/day,        no adverse effects               Scholz (1962)
                 5 days/week, 4 weeks
Cat (2)          23 (4000), 6 h/day, 5 days/week   no adverse effects               Clayton (1966)
Rat (12)         28 exposures
Guinea-pig (2)
Rabbit (1)

Rat (15)         58 (10 250), 8 h/day,             no compound-related effects      Jenkins et al. 
Guinea-pig (15)  5 days/week, 6 weeks                                               (1970)
Monkey (9)
Dog (2)

Rat (15)         5.7 (1008), 24 h/day,             no compound-related effects      Jenkins et al. 
Guinea-pig (15)  90 days                                                            (1970)
Monkey (9)
Dog (2)

Dog (6)          28.5 (5000), 6 h/day,             no adverse effects               Leuschner et al. 
                 90 days                                                            (1983)

Rat (40)         57.1 (10 000), 6 h/day,           no adverse effects               Leuschner et al. 
                 90 days                                                            (1983)


Cat (2)          503 (100 000), 3.5 h/day,         no adverse effects               Scholz (1962)
Rat (5)          5 days/week
Guinea-pig (3)
Dog (2)

Table 14.  (contd.)
Species and      Exposure                          Effects                          Reference
number of        g/m3a

Guinea-pig (15)  4.1 (810), 24 h/day,              fatty infiltration, necrosis     Prendergast et al.
Rat (15)         90 days                           in the liver of guinea-pigs,     (1967)
Dog (2)                                            no treatment-related effects
Monkey (3)                                         in other species

Guinea-pig (15)  4.1 (800), 8 h/day,               fatty infiltration,              Prendergast et al.
Rat (15)         5 days/week                       necrosis in the liver            (1967)
Rabbit (3)                                         of guinea-pigs, no 
Dog (2)                                            treatment-related effects
Monkey (3)                                         in other species

Dog              1006 (200 000),                   tremor, ataxia, dispnoea,        Sayers (1930)
Monkey           7-8 h/day                         salivation, lacrimation, 
                                                   no histological changes

Dog (6)          25 (5000), 6 h/day,               no adverse effects               Leuschner et al. 
                 90 days                                                            (1983)

Rat (40)         50 (10 000), 6 h/day,             no adverse effects               Leuschner et al. 
                 90 days                                                            (1983)

Rat              8.5 (1000), 18 h/day,             no toxic effects                 Clayton (1967a)
                 16 days
                 25 (3000), 4 h/day,               CNS and respiratory signs        Clayton (1967a)
                 10 days
Rat, mouse,      8.5 (1000), 6 h/day,              slight liver changes             Clayton (1967a)
guinea-pig,      31 days


Rat              16-31 (2000-4000),                changes in liver enzyme          Vainio et al. 
                 6 h/day, 7-14 days                activity, proliferation of       (1980)
                                                   smooth endoplasmic reticulum

Table 14.  (contd.)
Species and      Exposure                          Effects                          Reference
number of        g/m3a                                                                  

Rat, mouse,      16 (2000), 24 h/day,              no adverse effects               Trochimowicz 
dog, monkey      14 days                                                            (1984)

Monkey, rat      16 (2000), 24 h/day,              enlarged thyroids (monkey),      Carter et al. 
                 14 days                           increased kidney weight (rat)    (1970)

Mouse, dog       16 (2000), 24 h/day,              no adverse effects               Carter et al. 
                 14 days                                                            (1970)

Rat, guinea-pig  195 (25 000), 3.5 h/day,          no adverse effects               Trochimowicz 
                 20 exposures                                                       (1984)

Dog              97 (12 500), 3.5 h/day,           no adverse effects               Trockimowicz 
                 29 exposures                                                       (1984)

Rat, dog,        40 (5100), 6 h/day,               no adverse effects               Trochimowicz 
guinea-pig       20 exposures                                                       (1984)

Rat              16-22 (2075-2850), 7 h/day,       no adverse effects, reduced  
                 30 exposures                      rate of body weight gain, pale   Clayton (1966)
                                                   discoloration of the liver

Rat              up to 156 (20 000), 6 h/day,      no adverse effects               Trochimowicz 
                 5 days/week, 90 days                                               (1984)

Dog (6)          39 (5000), 6 h/day, 90 days       no adverse effects               Leuschner et al. 
Rat (40)         78 (10 000), 6 h/day,             no adverse effects               Leuschner et al. 
                 90 days                                                            (1983)


Cat, rat, dog,   711 (100 000), 3.5 h/day,         no adverse effects               Scholz (1962)
guinea-pig       20 exposures

Guinea-pig (6)   1002 (141 000), 8 h/day,          occasionally slight fatty        Yant et al. (1932)
                 21 days                           degeneration of the liver

Table 14.  (contd.)
Species and      Exposure                          Effects                          Reference
number of        g/m3a

Guinea-pig (6)   1422 (200 000), 8 h/day,          occasionally slight fatty        Yant et al. (1932)
                 4 days                            degeneration of the liver

Dog (3)          1002 (141 000), 8 h/day,          at study start incoordination,   Yant et al. (1932)
                 3-21 days                         tremor, occasionally 
                                                   convulsions; tolerance from
                                                   day 3-5 onwards

Dog (5)          1422 (200 000), 8 h/day,          100% mortality, temors,          Yant et al. (1932)
                 3-4 days                          convulsions, impaired body weight 
                                                   gain, haematological changes,
                                                   congestion of all organs

Rat (10)         711 (100 000), 2.5 h/day,         no adverse effects               Paulet & Desbrousses
Mouse (10)       5 days/week, 2 weeks                                               (1969)

Rat (10)         1422 (200 000), 2.5 h/day,        slight impairment of body        Paulet & Desbrousses
Mouse (10)       5 days/week, 2 weeks              weight gain increased lymphocyte (1969)
                                                   count, histopathology: alveolar 
                                                   and bronchiolar stasis

Rat (10)         71 (10 000), 2.5 h/day,           no adverse effects               Paulet & Desbrousses
Mouse (10)       5 days/week, 2 weeks                                               (1969)

Dog (6)          36 (5000), 6 h/day,               no adverse effects               Leuschner et al. 
                 90 days                                                            (1983)

Rat (40)         71 (10 000), 6 h/days,            no adverse effects               Leuschner et al. 
                 90 days                                                            (1983)


Rat, mouse,      642 (100 000), 6 h/day,           no adverse effects               Clayton (1966)
dog, rabbit      90 days
a  Values in parentheses are exposure concentrations in parts per million.
8.2.2.  Oral toxicity

    Repeated  dose studies of  less than 90 days  duration
have been reported for CFC-12, CFC-112, CFC-112a, CFC-114,
and  CFC-115  and generally  confirm  the low  toxicity of
these chlorofluorocarbons.

    In a study by Clayton (1967a), CFC-12 was given orally
to  rats at a  dose level ranging  from 160-379 mg/kg  per
day, as well as to dogs at doses of 84-95 mg/kg  per  day,
for  approximately  12 weeks  without significant  adverse
effects  related to nutritional, clinical,  laboratory, or
histopathological indices.

    Greenberg & Lester (1950) dosed rats with both CFC-112
and CFC-112a at 2000 mg/kg for 23-33 days with no clinical
or  histopathological evidence of toxicity.  However, when
rats  were given CFC-112 or CFC-112a at 5000 mg/kg per day
for  10 days, Clayton et  al. (1966) and  Clayton  (1967b)
found  that  both  chlorofluorocarbons  produced  tremors,
inactivity, initial weight loss, diarrhoea, a slight liver
weight  increase, and slight, reversible histopathological
changes in the liver.

    Like  CFC-112  and  CFC-112a, CFC-114  produced no ad-
verse effects in rats when administered at oral  doses  of
2000 mg/kg  per  day for  23-33 days (Quevauviller, 1965).
Clayton (1967a) also reported no evidence of  toxicity  in
rats given CFC-114 at 1300 mg/kg per day for 10 days.

    Clayton  (1966, 1967a) fed CFC-115 to rats at doses of
140-172 mg/kg  for 5 days/week for two weeks.  No clinical
or  histopathological effects were seen  immediately after
the last dose or two weeks later.

8.2.3.  Dermal toxicity

    McNight  & McGraw (1983)  investigated the effects  on
the  livers of hairless mice of dermal application of CFC-
113.   A pad saturated with CFC-113 was applied to an area
corresponding  to 10% of the body surface for 5 min, twice
daily, for 10, 20, or 40 days.  No changes occurred in the
group  exposed  for  10 days.  Increased  vacuolization of
liver  endoplasmic  reticulum  was seen  after 20 days ex-
posure,  which was less pronounced  after 40 days, whereas
swollen mitochondria were only found after 20 days exposure.

    CFC-113 applied to rabbit skin at 5 g/kg per day for 5
days caused gross and histological damage to the  skin  as
well as slight changes in the liver (Clayton, 1966).  CFC-
11, CFC-12, CFC-113, and CFC-114 at 40% in sesame oil were
sprayed onto shaved rabbit skin for 12 exposures  with  no
effect (Scholz, 1962).

    When  applied to the skin of rabbits at 7.5 g/kg, CFC-
112 caused skin erythema but no systematic or histological
effects. CFC-112a (11 g/kg) caused histological changes in
skin musculature and weight loss (Clayton, 1966).

8.3.  Skin and eye irritation; sensitization

    Severe  local irritation was produced  after 5 days by
CFC-113  kept occluded in liquified form at 5 g/kg per day
on shaved rabbit skin (Waritz, 1971).  Quevauviller et al.
(1964)  and  Quevauviller  (1965) applied  CFC-11, CFC-12,
CFC-114, and mixtures of CFC-11 and CFC-12 and  of  CFC-11
and  CFC-22 to the skin, tongue, soft palate, and auditory
canal  of rats, 1-2 times/day, 5 days/week, for 5-6 weeks.
The  same compounds were  applied once a  day, 5 days/week
for  1 month to the eye of rabbits.  Slight irritation was
noted only in the skin of the rats and in the eye  of  the
rabbits.   The healing rate  of experimental burns  on the
skin of rabbits, however, was noticeably retarded  by  all
of the compounds.

    When  applied to the skin  of rabbits, CFC-112 at  7.5
g/kg caused erythema and CFC-112a at 11 g/kg caused severe
skin  irritation, while CFC-113  at 11 g/kg produced  only
local irritation.  CFC-114 did not produce irritation when
sprayed  directly  on  the backs  of guinea-pigs (Clayton,
1966).  CFC-112 produced mild irritation  but no sensitiz-
ation  when applied to the skin of guinea-pigs (Clayton et
al., 1964).

8.4.  Long-term exposures

8.4.1.  Inhalation toxicity

    In  long-term inhalation toxicity  studies by Smith  &
Case  (1973),  mice and  dogs  were exposed  regularly for
brief periods to high levels of mixtures of  CFC-11,  CFC-
12,  CFC-114, and CFC-113 (25:49:25:1.1)  and CFC-11, CFC-
12, CFC-114, and Span 85, an emulsifier, (24.5:50:25:0.5),
respectively. In this study 30 female mice were exposed by
inhalation 5 days/week at levels of 0 or 970 mg/kg (calcu-
lated  value) per day for 23 months.  No signs of toxicity
were observed during the study and there was  no  evidence
of  lung tumours after  the 23 months of  exposure.   When
adult dogs (three of each sex) were exposed 7 days/week at
levels of 0 or 2240 mg/kg (calculated value) per  day  for
1 year,  some signs of toxicity, such as slight depression
or  drowsiness,  were  observed in  dogs immediately after
dosing  but lasted only a few minutes.  Tissue sections of
the  lungs did not  show signs of  toxicity or  irritation
from  inhalation. Also, no changes were observed in haema-
tology, blood chemistry, or urinalysis.

    Trochimowicz  et al. (1988)  performed a 2-year  inha-
lation  toxicity  and  carcinogenicity  study  of  CFC-113

(technical  grade,  purity  99.89%) on  Cr1:CD(SD)BR  rats
(Sprague  Dawley-derived).   Groups  of 100 males  and 100
females were exposed to 0, 15.3, 76.6, or  153 g/m3    (0,
0.2,  1, or 2% in  air) 6 h/day, 5 days/week, for  up to 2
years. Body weight, appearance and behaviour, and clinical
laboratory  values  (haematology, clinical  chemistry, and
urinalysis) were monitored regularly. Comprehensive histo-
pathological  examinations were performed  on rats in  the
control group and in those exposed to 153 g/m3.   The only
findings considered by the authors to be treatment-related
were decreases in mean body weight and in body weight gain
among  females exposed to  76.6 g/m3   and in  both  sexes
exposed to 153 g/m3,   and a slight, transient increase in
serum glucose levels in males exposed to 153 g/m3.

    When rabbits and rats were exposed for a period  of  2
years  (2 h/day,  5 days per  week)  to a  CFC-113 concen-
tration  of about 93 g/m3   (12 000 ppm), three out of six
rats  died.  In the exposed animals a slight dizziness was
observed.   Body  weight,  growth, and  haematology values
remained  unchanged.  No compound-related  effects on mor-
phology were found which could be attributed  to  exposure
to  CFC-113.  Also, since three  rats died in the  control
group  and  no treatment-related  signs  were seen  in the
surviving  animals exposed to  CFC-113, the deaths  of the
exposed  animals were probably not related to the exposure
(Desoille et al., 1968).

8.4.2.  Oral toxicity

    Long-term  oral toxicity studies have been carried out
on  CFC-11 and CFC-12.  NCI (1978) completed a bioassay of
CFC-11, administered by gavage in corn oil,  for  possible
carcinogenicity  in  Osborne-Mendel rats  and  B6C3F1 mice.
The  assay for carcinogenicity  was negative for  mice and
inconclusive  for rats.  Time-weighted average  doses were
488  and  977 mg/kg per  day for male  rats, 538 and  1077
mg/kg per day for female rats, and 1962 and 3925 mg/kg per
day for male and female mice.  All doses were administered
5 days/week.   In both male and female rats, a significant
(P < 0.001)  dose-related  acceleration  of mortality  was
noted compared with the vehicle control using  the  Tarone
test.  This increase in mortality occurred as early  as  4
weeks  in  the females  receiving  the higher  dose.  This
early  mortality, however, could not be related to changes
in  body weights, clinical signs, or non-tumour pathology.
Low  incidences (2-6%) of pleuritis  and pericarditis were
seen in the treated rats of both sexes at both dose levels
but  not in the control animals.  Chronic murine pneumonia
occurred in control and treated animals at  incidences  of
almost  90%.  In  mice, no  statistically significant com-
pound-related  effects were noted on weight gain, clinical
signs,  or non-tumour pathology.  In female, but not male,
mice,  a  significant  (P=0.009) dose-related  increase in
mortality  was  noted  compared with  the vehicle controls
using the Tarone test.

    Sherman  (1974)  conducted  long-term oral  studies of
CFC-12  on rats and dogs.   As part of a  multi-generation
reproductive and chronic toxicity study, groups of 50 male
and 50 female Charles River rats of the  F1a    generation
remained  in the test for 2 years, with an interim kill at
1 year.   Starting at 6 weeks of  age, controls, low-dose,
and  high-dose groups were administered CFC-12 in corn oil
or  corn oil alone daily by gavage for 6 weeks and 5 times
per week thereafter.  Over the course of the study, actual
daily doses of CFC-12 for low-dose males and  females  de-
clined  from 27 to 11 and 25 to 11 mg/kg per day, respect-
ively,  and, for the high-dose males and females, declined
from  273 to 130  and 242 to  128 mg/kg per day,  respect-
ively.  Average doses were 15 mg/kg per day for  the  low-
dose  groups  and  150 mg/kg  per  day  for  the high-dose
groups.  Body weight gain was depressed in  the  high-dose
groups,  particularly  among  the females,  and  a  slight
decline in food efficiency was noted in high-dose females,
relative  to controls.  No  overt signs of  toxicity  were
seen,  and there were  no significant differences  between
treated  and control groups in survival, periodic measure-
ments  of haematological, clinical chemistry,  and urinal-
ysis  values,  or  in organ  weights and histopathological
findings.  No evidence of carcinogenicity was seen.

    In the same study, groups of four male and four female
beagle dogs were orally administered CFC-12 (in frozen dog
food) at measured doses of 0, 8, or 80 mg/kg per day for 2
years.  None of the dogs died or showed signs of toxicity.
No  significant  differences  between treated  and control
groups were found in food consumption, body  weight,  per-
iodic  haematology, clinical chemistry and  urine testing,
organ  weights, or histopathological findings.  An adrenal
function  test (urinary 17-ketosteroid excretion) also re-
vealed  no  effects. There  was  no evidence  of  carcino-
genicity (Sherman, 1974).

8.5.  Reproduction and developmental toxicity

8.5.1.  Reproduction

    Effects  on  reproductive  parameters have  only  been
reported for two chlorofluorocarbons, CFC-12 and CFC-113.
    In a three-generation, oral gavage study in rats using
CFC-12  (in corn oil) at average doses of 15 and 150 mg/kg
per day, Sherman (1974) found no adverse effects on repro-
ductive  capability  as  measured by  the  fertility index
(percentage  of matings resulting in pregnancy), gestation
index  (percentage  of  pregnancies resulting  in birth of
live  litters), viability index  (percentage of rats  born
that  survived four days), and lactation index (percentage
of rats alive at 4 days that survived to be weaned  at  21

    In a limited one-generation reproduction study, groups
of  male  and  female  rats  were  exposed  by  inhalation
6 h/day,  5 days per week, for 10 weeks (males) or 3 weeks
(females)  to CFC-113 at  either 39 or  97 g/m3 (5000   or
12 500 ppm).  Each  male  rat  was  then  paired  with two
females  for  2 weeks  during  which  time  exposure   was
6 h/day,  7 days/week.  Females that showed positive signs
of  mating continued to be exposed 6 h/day until day 20 of
gestation when they were allowed to give birth. The devel-
opment  of their offspring was followed for up to 4 weeks.
There  were no  adverse effects  on any  of  the  standard
reproductive indices (US EPA, 1983).

8.5.2.  Developmental toxicity

    Of  the chlorofluorocarbons reviewed in this document,
developmental toxicity studies have been reported for CFC-
11, CFC-12, and CFC-113.

    In a study of a mixture (10% CFC-11 and  90%  CFC-12),
groups of rats and rabbits were exposed by  inhalation  on
days 4-16 (rats) or days 5-20 (rabbits) of  gestation  for
2 h/day  at a concentration of  1558 g/m3   (200 000 ppm).
No  evidence  of embryotoxicity,  fetotoxicity, or terato-
genicity was seen when rats and rabbits were sacrificed at
20 days  (rats)  or  30 days (rabbits)  of  gestation.  In
addition,  offspring  of the  dams  that were  allowed  to
deliver  naturally showed no evidence of toxicity relative
to survival or growth (US EPA, 1983).

    In  another study, groups of 25 to 27 pregnant Charles
River  rats  were given  CFC-12 in corn  oil by gavage  at
doses  of 16.6 or 179 mg/kg  per day on days  6-15 of ges-
tation.  Neither dose induced  any evidence of  embryotox-
icity or teratogenicity (Sherman, 1974).

    Three  unpublished  studies  on rats  and rabbits were
carried  out using CFC-113 and were reviewed by the US EPA
(1983).  Groups of 24 pregnant rats were  exposed  6 h/day
on  days 6-15 of gestation  to either 39, 97,  or   195 g/m3
(5000,  12 500, or 25 000 ppm  in air).  Some  evidence of
maternal  toxicity  (reduced  weight gain,  decreased food
intake)  was seen at the highest exposure level.  However,
there  was no evidence of embryotoxicity, fetotoxicity, or
teratogenicity at any exposure level.

    Two studies using rabbits were judged to be inadequate
by the US EPA (1983) because of the small number  of  dams
and fetuses evaluated, the limited exposure time each day,
and  excessive  maternal  toxicity.  In  the  first  study
(Hazleton  Laboratories, 1967a), groups of 12 rabbits were
exposed to CFC-113 at either 15.6 or 156 g/m3    (2000  or
20 000 ppm  in air) for 2 h/day on days 8-16 of gestation.
Signs  of  maternal  toxicity  were  seen  at  the highest
exposure level but there was no evidence of embryotoxicity
or teratogenicity attributable to CFC-113.

    In  the  second  rabbit study  (Hazleton Laboratories,
1967b),  groups  of eight  rabbits  were given  CFC-113 at
either 1000 or 5000 mg/kg per day by gavage on  days  8-11
of  gestation. No unusual skeletal  or visceral abnormali-
ties were observed at either dose level, but low pregnancy
rates  and fetal  deaths were  seen in  control  and  test

    In  conclusion, none of the  three chlorofluorocarbons
tested  (CFC-11, CFC-12, and CFC-113) show any evidence of
reproductive  or developmental toxicity. There  is no sig-
nificant  information on this subject for any of the other
chlorofluorocarbons evaluated in this monograph.

8.6.  Mutagenicity and related end-points

    The  mutagenic  potential  of the  chlorofluorocarbons
reviewed  in this monograph has  been evaluated, primarily
using   the  Salmonella assay   (Uehleke   et  al.,   1977;
Longstaff  et al., 1984) with  negative results.  Negative
results were also obtained for CFC-11, CFC-12, and CFC-115
in  a cell transformation  assay (Longstaff et  al., 1984)
and for CFC-11 and CFC-12 in a mammalian cell mutagenicity
test  (Krahn et al., 1982).   CFC-12 was also tested  in a
plant  assay using  Tradescantia,  and found to be negative
(Van't Hof & Schairer, 1982).

    A  dominant lethal assay  was performed as  part of  a
reproduction study on rats using CFC-12 at doses of 15 and
150 mg/kg  per  day  (gavage) for  several weeks (Sherman,
1974).   Another dominant lethal assay  was performed with
CFC-112  and CFC-113 on mice  after single intraperitoneal
injections of 200 and 1000 mg/kg (Epstein et  al.,  1972).
Negative  results were obtained  in both of  these  in vivo
assays.   The mutagenicity studies are summarized in Table

8.7.  Carcinogenicity

    Long-term oral carcinogenicity studies of CFC-11 (NCI,
1978)  and CFC-12 (Sherman,  1974) gave negative  results.
When  administered by gavage to  groups of 50 male and  50
female B6C3F1 mice  (see section 8.4.2), CFC-11 at 1962 or
3952 mg/kg per day, 5 days/week, for 78 weeks, followed by
13 weeks  of observation, produced no evidence of carcino-
genicity  (NCI, 1978).  Gavage administration of CFC-11 to
groups of 50 male and 50 female Osborne-Mendel rats in the
same  study also produced no  evidence of carcinogenicity,
but  the results were considered to be inconclusive by the
NCI  (1978)  because the  numbers  of rats  surviving long
enough  to be at  risk from late-developing  tumours  were
insufficient.   In this study, time-weighted average doses
of CFC-11 (488 and 977 mg/kg per day for male rats and 538
and  1077 mg/kg per day for female rats) were administered
5 days/week  for  78 weeks,  followed  by  28-33 weeks  of

CFC-11    Reverse mutationa (L)     S. typhimurium  TA1535   yes          negative    Uehleke 
CFC-11    Reverse mutationa (L)     S. typhimurium  TA1538   yes          negative    et al. (1977)

CFC-11    Reverse mutation (G)      S. typhimurium  TA100    no/yes       negatived   Longstaff et 
                                                   TA1535   no/yes       negative    al. (1984)

CFC-11    Forward mutation (G)     CHO cells       NA       no/yes       negative    Krahn et al. 

CFC-11    Cell transformation (G)  BHK21 cells     NA       yes          negative    Longstaff et 
                                                                                     al. (1984)

CFC-12    Reverse mutation (G)      S. typhimurium  TA100    no/yes       negatived   Longstaff et 
                                                   TA1535   no/yes       negative    al. (1984)

CFC-12    Forward mutation (G)     CHO cells       NA       no/yes       negative    Krahn et al. 

CFC-12    Cell transformation (G)  BHK21 cells     NA       yes          negative    Longstaff et 
                                                                                     al. (1984)

CFC-12    Forward mutation (G)     Trandescantia   Clone    NA           negative    Van't Hof & 
          Blue locus               hybrid          4430c                             Schairer, (1982)

CFC-12    Dominant lethal          ratsb           Charles  NA           negative    Sherman (1974)
          mutation (g.i.)                          River CD NA           negative

CFC-13    Reverse mutation (G)      S. typhimurium  TA100    no/yes       negatived   Longstaff et 
                                                   TA1535   no/yes       negative    al. (1984)

Table 15.  (contd.)
Compound  Method or type of        Organisms       Strain   Use of       Results     Reference
(code)    assay (exposures)                                 metabolic 

CFC-112   Dominant lethal          Swiss miceb     ICR/Ha   NA           negative    Epstein et 
          mutation (i.p.)                                                            al. (1972)

CFC-113   Reverse mutation (G)      S. typhimurium  TA100    no/yes       negatived   Longstaff et 
                                                   TA1535   no/yes       negative    al. (1984)

CFC-113   Dominant lethal          Swiss miceb     ICR/Ha   NA           negative    Epstein et 
          mutation (i.p.)                                                            al. (1972)

CFC-114   Reverse mutation (G)      S. typhimurium  TA15351  no/yes       negatived   Longstaff et 
                                                                                     al. (1984)

CFC-115   Reverse mutation (G)      S. typhimurium  TA1535   no/yes       negatived   Longstaff et 
                                                                                     al. (1984)

CFC-115   Cell tranformation (G)   BHK21 cells     NA       yes          negative    Longstaff et 
                                                                                     al. (1984)
a   Ames assay performed with pre-incubation for 60 min in closed vials under nitrogen gas.
b   See text for dose information.
c   Heterozygous for blue locus.
d   Longstaff et al. (1984) stated that all the fluorocarbons tested gave negative results in 
     S. typhimurium TA1538 and TA98 in the absence or presence of a metabolic activating system.
NA = not applicable; G = gas; L = liquid; g.i. = gastric intubation; i.p. = intraperitoneal; 
BHK21 = permanent cell line of baby hamster kidney fibroblasts; CHO = Chinese hamster ovary; 
HGPRT = hypoxanthine guanine phosphoribosyl transferase.
    CFC-12  administered by gavage at  doses of 15 or  150
mg/kg  per  day for  2 years to groups  of 50 male and  50
female  Charles  River rats  of  the F1a generation   in a
multi-generation  study  (see  section 8.4.2) produced  no
evidence of carcinogenicity (Sherman, 1974).

    Data   on  the  carcinogenicity of  inhaled CFC-11 and
CFC-12  by Sprague-Dawley rats  and Swiss mice  have  been
reported by Maltoni et al. (1988).  When  administered  to
groups  of 90 male and 90 female  rats and 60 male and  60
female mice at concentrations of 1000 or 5000 ppm  (57  or
285 g CFC-11/m3;    49  or 247 g CFC-12/m3),    4 h/day, 5
days/week,  neither  compound  was found  to  have induced
statistically  significant differences in the incidence of
total  benign  or  malignant tumours  when  compared  with
groups of unexposed rats or mice.  The authors also stated
that the incidence of all tumours and of some particularly
frequently  occurring spontaneous tumours in mice showed a
tendency to increase in animals exposed to CFC-11 and CFC-
12 and that the increased incidence was  usually  observed
in one sex and was not always dose related,  possibly  due
to  a longer survival  of the treated  mice compared  with

    Trochimowicz  et al. (1988)  conducted a 2-year  inha-
lation  toxicity and carcinogenicity  study of CFC-113  in
Cr1:CD(SD)BR rats.  In this study, groups of 100 males and
100 females  were  exposed  to CFC-113  (technical  grade,
purity  99.89%) at 0, 152,  760, or 1520 g/m3   (0,  2000,
10 000,  or 20 000 ppm), 6 h/day, 5 days/week, for up to 2
years. The toxic effects, which were minimal, are reviewed
in section 8.4.1.  Primary nasal tumours were found in one
male  rat exposed to 1520 g/m3 and  in three male rats and
one  female  rat exposed  to  760 g/m3.   The  five  nasal
tumours were classified as an adenoma, an undifferentiated
sarcoma,  an  early carcinoma,  a carcinoid-like neoplasm,
and a papilloma.  The authors noted that spontaneous nasal
tumours were rare in the control rats. Female rats exposed
to 1520 g/m3 showed  a statistically significant increase,
relative to control females, in the incidence  of  pancre-
atic islet cell adenomas.  The incidence of this tumour in
the females of the highest dose group was  5.8%.   Because
the  nasal tumours found in the treated rats were of vari-
ous morphological types and the incidences were  not  dose
related, the authors concluded that the occurrence of this
tumour was not related to CFC-113 exposure.   However,  as
indicated in section 8.3, CFC-113 is a local  irritant  at
high concentrations. Thus the neoplasms found in the nasal
cavity  may  be the  consequence  of the  local irritation
caused by CFC-113 in the peculiar anatomical configuration
of  this cavity in the rat. In addition, because the inci-
dence  of pancreatic islet  cell adenomas in  the  females
exposed  to 1520 g/m3   was "within the anticipated inci-
dence of this finding among untreated Cr1:CD(SD)BR rats,"

the increased incidence in this group, relative to matched
controls,  was  not considered  to  be related  to CFC-113

    CFC-112  and CFC-113, at  a dose of  0.1 ml 10%  (v/v)
solution injected subcutaneously into the neck of neonatal
mice,  were not carcinogenic.   However, when injected  in
conjunction   with  a  5%  (v/v)   solution  of  piperonyl
butoxide, hepatomas were induced in male mice.   This  was
particularly marked with CFC-113. The apparent synergistic
hepatocarcinogenicity  of  these chlorofluorocarbons  with
piperonyl  butoxide cannot be  explained at present.   The
investigators  speculated  that  piperonyl  butoxide   may
interfere  with  the  metabolism  of   chlorofluorocarbons
(Epstein  et al., 1967a).  The significance of this effect
is difficult to interpret because of the lack of follow-up
studies in other species (Tomatis et al., 1973)  and  with
other chlorofluorocarbons.

8.8.  Special studies - cardiopulmonary effects

8.8.1.  Cardiac sensitization in response to exogenous adrenaline-induced 

    A  variety of hydrocarbons,  with and without  halogen
substitution,  have long been known to sensitize the heart
to  adrenaline-induced  arrhythmias including  ventricular
fibrillation  (Hermann  &  Vial, 1935;  Garb  & Chenoweth,
1948; Hays, 1972; Reinhardt et al., 1973). At various con-
centrations,   chlorofluorocarbons  have  been   shown  to
produce  this effect.  Because this  arrhythmogenic action
may  be related to  a variety of  human health hazards,  a
great deal of research has been stimulated in  this  area,
focused primarily on determining the minimum concentration
of  chlorofluorocarbons and adrenaline required to produce
arrhythmias in various mammals.  The reader is referred to
Zakhair  & Aviado (1982) for a review of the literature on
this subject.

    Reinhardt  et al. (1971b) exposed dogs to varying con-
centrations  of CFC-12 for periods of 0.5-10 min and found
that  a minimum  concentration of  CFC-12 in  air  of  250
g/m3    (5%) was necessary  to sensitize the  heart to  an
intravenous dose of adrenaline (8 µg/kg   body weight) and
that  increasing the period  of exposure to  lower concen-
trations   did   not  result   in  arrhythmias.   However,
increasing  the chlorofluorocarbon concentration  resulted
in  a reduction of the sensitizing concentration threshold
of exogenous adrenaline. In dogs exposed to normal oxygen-
ation  and  CFC-12  at 500 g/m3 (10%)   (which resulted in
75 µg  CFC-12/ml in arterial blood), the exogenous adrena-
line  concentration related to arrhythmia was 3 µg/kg  per
min, while it was only 2.5 µg/kg  per min at a CFC-12 con-
centration  of 1000 g/m3 (20%)  (resulting in 155 µg  CFC-
12/ml in arterial blood) (Lessard et al., 1977b).  For the

same  CFC-12 concentration (1000 g/m3,   20%, resulting in
155 µg/ml   in  arterial  blood), arrhythmias  occurred in
rabbits only at the concentration of 8 µg/kg  per  min  of
exogenous   adrenaline,   the   arrhythmogenic   threshold
depending  also  on the  animal  species (Lessard  et al.,
1977a).  For the most part, the comparative arrhythmogenic
potencies  of  chlorofluorocarbons  are similar  to  those
noted  in  standard  inhalation studies:  as  fluorination
increases  within a homologous  series, toxicity tends  to
decrease. Thus, for the chlorofluoromethanes, the arrhyth-
mogenic potency of CFC-11 seems to be greater than that of
CFC-12. A similar pattern is seen in the fully halogenated
ethanes  (CFC-113 > CCF-114 > CFC-115) (Reinhardt et  al.,
1971b, 1973; Clark & Tinston, 1972a,b; Wills, 1972).

    That  a critical blood level  of chlorofluorocarbon is
needed  to cause sensitization indicates  that differences
among  the chlorofluorocarbons may primarily  reflect dif-
ferences  in  absorption  characteristics rather  than any
toxic  mechanisms  on  the molecular  level  (Jack,  1971;
Taylor  et al., 1971; Clark & Tinston, 1972a; Azar et al.,
1973).  The  similarities  in lowest  venous blood concen-
trations  associated  with cardiac  sensitization in these
various  studies  suggest that  these  compounds act  in a
similar   and  perhaps  non-specific  manner   in  causing
arrhythmias.  This type of speculation is at least circum-
stantially  supported by the basic similarities in cardiac
effects  caused by these and other halo-substituted hydro-

8.8.2.  Cardiac sensitization and asphyxia-induced arrhythmia

    Studies  by  Taylor  & Harris  (1970a)  indicated that
inhaled  chlorofluorocarbons  are  toxic to  the hearts of
mice, as shown by the rapid onset of sinus bradycardia and
atrioventricular (AV) block induced by a degree of partial
asphyxia  sufficient  to  cause tachycardia  in  unexposed
mice.   However, four other groups  of investigators (Azar
et al., 1971; Jack, 1971; Egle et al., 1972; McLure, 1972)
failed  to confirm these  findings.  They found  that  the
effects caused by chlorofluorocarbons do not vary signifi-
cantly  from those caused  by nitrogen asphyxia  controls.
These  authors concluded that the bradycardia and AV block
were  actually due to asphyxia,  not to chlorofluorocarbon
exposure.   Although  the preceding  controversy was never
resolved,  it is important  to note that  no reports  have
been  found  that  confirm the  work  of  Taylor &  Harris

    The  mechanism by which  arrhythmia is related  to the
severity of asphyxia is at present unknown.   However,  it
may  be related to the degree of adrenaline stimulation or
myocardial  depression  associated  with a  given level of
asphyxia (Zakhair & Aviado, 1982).  This mechanism is also
probably  related to the nature of the chlorofluorocarbon,

since induced changes in heart rate depend  on  chloroflu-
orocarbon  concentrations  and  the animal  species.   For
example, inhalation of CFC-12 (concentrations of CFC-12 in
gas  mixture are given in  brackets; animals anaesthetized
unless stated otherwise) has been reported to cause:

*   bradycardia in mice (1006 and 2012 g/m3,   i.e. 20 and
    40%)  (Aviado & Belej, 1974),  rats (1006 g/m3,   20%)
    (Doherty  & Aviado, 1975), and dogs (concentration not
    given) (Flowers & Horan, 1972);

*   no  change in  cardiac rate  in monkeys  (251 and  503
    g/m3,    i.e. 5 and  10%) (Belej et  al., 1974),  rats
    (from  0-2515 g/m3,   i.e. 0 to 50%) (Friedman et al.,
    1973),  cats (1257 g/m3,   25%) (Harris et al., 1971),
    or  rats (503, 1006, and 2012 g/m3,   i.e. 10, 20, and
    40%) (Watanabe & Aviado, 1975);

*   tachycardia  in  monkeys (251-503 g/m3,    i.e. 5-10%)
    (Aviado  &  Smith)  and in  unanaesthetized rats (503,
    1006,  and 2012 g/m3,   i.e. 10, 20 and 40%) (Watanabe
    & Aviado, 1975).

    According  to  Lessard  et al.  (1977a), CFC-12 causes
tachycardia  in anaesthetized rabbits at concentrations of
1006 g/m3 (20%)  or more and in anaesthetized dogs at con-
centrations of 503 g/m3   (10%) or more (Lessard  et  al.,
1977b). After surgical removal of baroreceptors in rabbits
and  dogs, CFC-12 at any concentration causes bradycardia.
Thus, the tachycardia is due to the  baroreflex  secondary
to  the fall in arterial  blood pressure (Lessard et  al.,

    Hypoxia  is  also  known to  potentiate the myocardial
depression due to CFC-12 in isolated papillary  muscle  of
rats  (Kilen  & Harris,  1972, 1976) and  in the heart  of
anaesthetized rabbits (Taylor & Drew, 1974).

    Hypoxia  associated with high concentrations of CFC-12
(4778 g/m3,   i.e. 95%, in gas mixture or  1475 µg/ml   in
arterial  blood) is needed  to cause fatal  arrhythmia  in
anaesthetized dogs (Flowers & Horan, 1975).

8.8.3.  Arrhythmia not associated with asphyxia or adrenaline

    Some  chlorofluorocarbons  have  been found  to affect
cardiac  function under conditions of adequate oxygenation
or  in the absence of elevated adrenaline levels. Arrhyth-
mia, in the absence of hypoxaemia or hypercarbia, has been
demonstrated  in dogs (CFC-12, 3974 g/m3,    i.e. 79%, re-
sulting in 725 µg/ml  in arterial blood, Lessard  et  al.,
1978; CFC-12 concentration not mentioned, Flowers & Horan,
1972),  monkeys  (CFC-12, 1509 g/m3,    30% + CFC-114, 453
g/m3 (9%):  Taylor et al., 1971) and rabbits  (79%  CFC-12
resulting in 855 g/ml in arterial blood: Lessard  et  al.,

1978).   However, Lessard et al. did not obtain arrhythmia
in  either dogs or  rabbits, exposed to  the same  concen-
trations  of CFC-12, after surgical  removal of barorecep-
tors,  showing  that  these arrhythmias  were  related  to
reflex  endogenous  adrenaline  delivery (Lessard  et al.,

8.9.  Mechanisms of toxicity - mode of action

    Studies  concerning  cardiac  arrhythmias  caused   by
chlorofluorocarbons  at  high concentrations  (see section
8.8) may be interpreted in two ways (Taylor et al., 1971).
Firstly, the chlorofluorocarbon gases may be exerting some
direct  effect on the myocardium.  Secondly, they may have
sensitized   the  ventricular  myocardium   to  endogenous
catecholamines  (see Aviado &  Belej, 1974).  This  latter
interpretation is consistent with the blocking of arrhyth-
mias by propranolol. The two interpretations are supported
by  the more  recent results  of Lessard  et  al.  (1980),
Lessard  & Paulet (1985), and Lessard & Paulet (1986).  On
the  basis  of  an electrophysiological  analysis  of  the
action  of CFC-12 on different types of cardiac cells from
rats and sheep, these authors conclude that:

*   the  cardiac depression observed during  inhalation of
    CFC-12 (and many other volatile liposoluble compounds)
    is the consequence of a non-specific impairment of the
    membrane  properties  and  notably the  inhibition  of
    trans-membrane ionic currents;

*   CFC-12 action on ionic currents is variable:  at  high
    concentrations, depending on the type of cardiac cell,
    it  can  oppose or  favour  the action  of adrenaline,
    giving rise to many factors that lead to arrhythmia.

    In  a review of  the toxicity of  chlorofluorocarbons,
Aviado (1978) proposed a combination of mechanisms for the
cardiopulmonary  effects of fluorocarbons.  Disintegration
of  normal alveolar surfactant was implicated in the death
of  an  adolescent  after abuse  of  a chlorofluorocarbon-
propelled aerosol (Fagan et al., 1977).

    Several  investigators have attempted to  determine if
chlorofluorocarbons   affect   oxidative  phosphorylation.
Griffin  et al. (1972) showed  that CFC-12 and CFC-114  do
not   markedly  affect  oxygen  consumption  or  oxidative
phosphorylation  in mitochondria isolated from  the liver,
lung,  brain, heart, or  kidney of rats  exposed to  about
7.5% chlorofluorocarbons prior to mitochondrial isolation.
Further  in  vitro studies  were  conducted with  liver and
heart mitochondria in which measurements were taken during
exposure of the mitochondria to CFC-12 at 990 g/m3   (20%)
(time  of exposure not  specified).  No effects  on either
oxidation  or phosphorylation were noted  (Griffin et al.,


9.1.  Controlled studies with volunteers

    The  studies  reported by  Stewart  et al.  (1978) are
among  the more comprehensive attempts to characterize the
effects  of CFC-11 and  CFC-12 on human  volunteers  under
controlled conditions.  A number of biological end-points,
including  clinical  haematology and  chemistry, ECG, EEG,
pulmonary function, neurological parameters, and cognitive
tests  were monitored.  Single exposures to CFC-11 or CFC-
12  at concentrations of 0.025%  (CFC-11, 1.4 g/m3;   CFC-
12,  1.2 g/m3),    0.05% (CFC-11,  2.8 g/m3;   CFC-12, 2.5
g/m3),  and  0.1% (CFC-11,  5.6 g/m3;   CFC-12,   5 g/m3),
for 1 min to 8 h, induced no observable effects. There was
a  statistically-significant  decrease  in cognitive  test
performance in subjects exposed to CFC-11 at 5.6 g/m3,   8
h/day, 5 days/week, for 2-4 weeks, but not in subjects ex-
posed to CFC-12 at 5 g/m3.   Although the authors regarded
this  effect as "spurious", the similar effects observed
on  acute exposures to CFC-12  (Kehoe, 1943; Azar et  al.,
1972)  and CFC-113 (Stopps & McLaughlin, 1967), as well as
the  behavioural effects of  CFC-21 on baboons  (Geller et
al., 1977), suggest that psychomotor impairment may  be  a
general  effect of fluorocarbons, which  precedes signs of
definite toxic effects.

    Kehoe  (1943) exposed one subject to CFC-12 at concen-
trations   of  198 g/m3 (4%),   297 g/m3 (6%),    347 g/m3
(7%),  and 545 g/m3   (11%) for periods of 80, 80, 35, and
11 min,  respectively. A second subject was exposed to 198
g/m3    for 14 min, immediately followed by 99 g/m3   (2%)
for  66 min.   At  198 g/m3,   the  subject  experienced a
tingling sensation, humming in the ears, and apprehension.
EEG changes were noted as well as slurred speech  and  de-
creased performance in psychological tests. In the subject
exposed to higher concentrations, these signs and symptoms
became  more  pronounced with  increases in concentration.
An  exposure to 545 g/m3   for 11 min caused a significant
degree  of cardiac arrhythmia,  followed by a  decrease in
consciousness  with  amnesia  after 10 min.   At a concen-
tration  of 50 g/m3   (1%) for 150 min, Azar et al. (1972)
noted  a 7% decrease  in psychomotor test  scores, but  no
effect  at 5 g/m3   (0.1%) over the same period.  Valic et
al. (1977) exposed 10 subjects to CFC-11, CFC-12, CFC-114,
two mixtures of CFC-11 and CFC-12, and a mixture of CFC-12
and  CFC-114 (breathing concentrations between  16 and 150
g/m3)   for 15, 45, or 60 seconds, and  found  significant
acute  reduction  of  ventilatory  lung  capacity  (FEF50,
FEF25)  on exposure to each chlorofluorocarbon, as well as
bradycardia  and  increased  variability in  heart rate in
seven  subjects, negative T-waves in two subjects (one was
exposed  to CFC-11 and CFC-12), and atrioventricular block
in  1 subject (CFC-114). Mixtures exerted stronger respir-
atory  effects  than individual  chlorofluorocarbon at the
same level of exposure.

    In  another  study,  11 subjects (7 being  maintenance
technicians  of  large cooling  and refrigerating systems)
were  exposed  for  130 min to  CFC-12  (weighted exposure
0.46,  49.9,  and  87.7 g/m3),   HCFC-22  (0.71  and  18.9
g/m3),    and CFC-502 (a  mixture of 4 g  CFC-115/m3   and
1.4 g  CFC-22/m3 or  of 23.4 g CFC-115/m3 and  10.5 g CFC-
22/m3).    This led to acute reduction of ventilatory lung
capacity  only at the  two highest CFC-12  concentrations,
under which conditions a significant decrease in the heart
frequency was also observed (Valic et al., 1982).

    CFC-113  has been tested on human subjects by Stopps &
McLaughlin  (1967) and Reinhardt et  al. (1971a).  Psycho-
motor performance was evaluated with exposures to  12 g/m3
(0.15%),  19 g/m3 (0.25%),  27 g/m3 (0.35%),  and  35 g/m3
(0.45%) for 165 min (Stopps & McLaughlin, 1967).   At  the
lowest  level, no effect was noted, but at 19 g/m3   there
was  difficulty in concentrating and some decrease in test
scores.   These effects were  more pronounced at  27 g/m3,
and at 35 g/m3 performance  in various tasks was decreased
by between 10 and 30%. These decreases coincided with sen-
sations  of "heaviness" in  the head, drowsiness,  and a
slight  loss of orientation  after shaking the  head  from
left to right. Reinhardt et al. (1971a) exposed four human
subjects  to CFC-113 at concentrations  of 8 g/m3   (0.1%)
and 4 g/m3 (0.05%)  for 180-min periods in the morning and
afternoon  on 5 days.  No decreases in psychomotor ability
were  noted.  No abnormal findings were noted during post-
exposure  physical  examination, haematological  and blood
chemistry  tests (conducted 3 days after  final exposure),
and  steady-state  measurements  of diffusing  capacity of
lungs and fractional uptake of carbon monoxide.

    Skuric  et al. (1975) exposed  17 volunteers for 2 min
to  8 household  sprays  containing  CFC-11  (19-54 g/m3),
CFC-12 (12-106 g/m3),   or both. They observed significant
reductions  in  ventilatory  lung capacity  in  each  case
(relative  reductions:  FEV1, 3.3-7.4%;  FEF50, 5.3-11.2%;
FEF25,  12.1-20.9%).  However, the reductions  on exposure
to  sprays were greater  than those measured  in  separate
exposures  to  chlorofluorocarbons only  (at corresponding
breathing  concentrations),  suggesting  that other  spray
components were mainly responsible for the changes in ven-
tilatory  function.  Similar findings of acute ventilatory
capacity   reductions  on  exposure  to  hair-sprays  were
described by Zuskin et al. (1974, 1981) and Swift  et  al.
(1979),  but  exposure  levels  were  not  given  in these

    Graff-Lonnevig  (1979) reported a study of the effects
of  chlorofluorocarbons  on bronchiolar  tone in asthmatic
children.   Forced expiratory volume  (FEV), a measure  of
bronchial tone, was measured in 18 children with a history

of asthma, before and after inhaling aerosols  of the  ß2-
receptor  agonist, fenoterol, or a mixture of CFC-11, CFC-
12,  and CFC-114, and  in the absence  of treatment.   The
levels  of exposure were  not reported.  Exposure  to  the
chlorofluorocarbon  mixture significantly reduced  FEV for
2 h, relative to "no treatment", and for 8 h relative to
exposure  to fenoterol (containing CFC-11 and CFC-12). The
results  suggest  that  chlorofluorocarbons  can  decrease
bronchial tone in asthmatic patients, but that this effect
is transient and of a sufficiently small magnitude  to  be
superseded  by the dilating effects of fenoterol when both
fenoterol  and chlorofluorocarbon propellants  are inhaled

    Van  Ketel (1976) reported allergic  contact eczema in
patch tests performed on three patients that had  a  prior
history  of skin reactions to deodorant sprays.  All three
patients  showed strong positive reactions to 11 deodorant
sprays and mild to strong reactions to CFC-11. One patient
showed  a mild reaction to CFC-12. Fifteen controls (with-
out  prior  history of  allergy  to deodorants)  showed no
response to either CFC-11 or CFC-12. These results suggest
that  individuals may become sensitized to certain chloro-
fluorocarbons applied repeatedly to the skin surface.

9.2.  Occupational exposure

    Two  studies  (Imbus  &  Adkins,  1972;  NIOSH,  1980)
suggest that frequent occupational exposures to CFC-113 do
not  pose  a serious  health  hazard.  No  adverse effects
occurred  at levels as  high as 36.7 g/m3    (0.478%)  and
averaging 5.4 g/m3 (0.07%).

    Significant  acute reductions in the  ventilatory lung
capacity during a work shift of hairdressers using chloro-
fluorocarbon-containing  hair-sprays were observed in sev-
eral  studies (Zuskin & Bouhuys, 1974; Valic et al., 1974;
and Zuskin et al., 1974).

    Several  cases of accidental death attributed to occu-
pational   exposure   to  chlorofluorocarbons   have  been
reported.  May & Blotzer (1984) described three  cases  of
death from exposure to CFC-113. In each case, the individ-
uals  succumbed to high concentrations  of CFC-113 vapour.
A level of 997 g/m3   (128 000 ppm) was estimated  in  one
case and, in another, death occurred within  15 min  after
exposure to an estimated 47-288 g/m3 (6000-37 000 ppm).

    Cases  of  neurological  effects attributed  to  occu-
pational  exposure  to  chlorofluorocarbons have  been re-
ported. Raffi & Violante (1981) described a case of neuro-
pathy  in a laundry worker  exposed to tetrachloroethylene
for  6 years  and to  undetermined  levels of  CFC-113 for

7 years prior to reporting symptoms. Both dermal and inha-
lation  exposure probably occurred. The individual experi-
enced  pain, paraesthesia and  weakness of the  legs,  and
decreased   motor  nerve  conduction  velocity.   She  was
instructed  to avoid contact with CFC-113 and to rest; her
clinical  condition  improved  without  treatment  in  one

    A similar case concerning a refrigerator repair worker
was reported by Campbell et al. (1986).  Symptoms included
pain,  paraesthesia,  and weakness  in  the legs,  and low
nerve  conduction  velocities.  The  case was subsequently
followed  up  with  a  study  of  27 refrigerator   repair
workers. The refrigerator workers and a reference group of
14 pipe  fitters and insulators were given a medical exam-
ination  that  included  measurements of  nerve conduction
velocities.  The refrigerator workers reported  a signifi-
cantly  elevated incidence of "lightheadedness" and pal-
pitations,  but  no  differences in  nerve conduction vel-
ocities were observed.

    In  another  study,  89 workers were  examined  during
their  work with refrigerant equipment.   The refrigerants
used  were mainly CFC-12 (in 56% of the cases) and HCFC-22
(32%), the rest being CFC-11, CFC-500 (a mixture of CFC-12
and  HCFC 152a),  and CFC-502  (a mixture  of CFC-115  and
HCFC 22). The mean exposure time was 10 min. Chlorofluoro-
carbon  concentrations in the breathing zone were measured
for each person individually.  The levels exceeded 750 ppm
at least once (as one minute mean values) for 60 of the 89
individuals.   Cardiac arrhythmias were registered before,
during,  and after the exposure by means of a portable ECG
instrument connected to a tape recorder.  No statistically
significant  difference was found between exposed and non-
exposed  periods, nor was there any dose-related trend for
different individuals when grouped into different exposure
groups.   In this study,  possible effects on  the central
nervous  system were also studied by means of simple reac-
tion  time measurements before and after the exposure.  No
impairment was seen (Edling & Ohlson, 1988).

    Szmidt  et al. (1981)  investigated death rates  among
539 workers  exposed  occupationally  in constructing  and
repairing refrigeration equipment. The chlorofluorocarbons
used  were CFC-12, HCFC-22, and CFC-502 (a mixture of CFC-
115  and HCFC-22).  No increase in total deaths (18 cases)
was seen among those employed more than 6 months, compared
to the expected number (26 cases), nor was there any stat-
istically  significant increase in total  tumour deaths or
deaths  caused by lung cancer  or cardiovascular diseases.
When  the study was restricted  to those exposed for  more
than  3 or 10 years,  still no significant  increases were
seen.  No data on exposure levels were given.

    Thomas  (1965)  reported  that workers  who  spilled a
large volume of CFC-11 were exposed to high concentrations
and  developed narcotic effects. In one case, unconscious-
ness occurred, and in another, potentiation of  the  endo-
genous adrenaline effect and tachycardia.

    Yonemitsu  et al. (1983) reported  an industrial acci-
dental  death due to exposure to CFC-113 used as a solvent
for  cleaning a washer  tub filter.  A  large quantity  of
liquid CFC-113 was found at the bottom of the  washer  tub
in which the filter had been cleaned.   The  concentration
of  the CFC-113 was  935-1091 g/m3   (12-14%).  Death  was
attributed  to inhalation of the  highly concentrated CFC-
113 vapour in the washer room.

    The  US National Institute for Occupational Safety and
Health  (May  &  Blotzer,  1984)  reported  the  deaths of
12 workers  due  to  asphyxiation  or  cardiac  arrhythmia
resulting  from excessive occupational exposure to CFC-113
while  working  in confined  spaces  or areas  with insuf-
ficient  ventilation.   Uncontrolled  use of  CFC-113 as a
solvent  was  reported  as  the  primary  cause  for these
deaths.  This report contains recommendations for control-
ling exposure to CFC-113.

9.3.  Non-occupational exposures

    Only  two cases of accidental  ingestion of chloroflu-
orocarbons  have  been reported.   Clayton (1966) reported
that 1 litre of CFC-113 was accidentally released into the
stomach  of  an  anaesthetized patient,  causing transient
cyanosis.   For the next  3 days, the patient  experienced
severe rectal irritation and diarrhoea.

    A study by Marier et al. (1973) involved a group of 20
housewives who were given 13 household products containing
chlorofluorocarbon  propellant  (CFC-11, CFC-12,  and CFC-
114) to be used during 4 weeks in conformity with  a  pre-
scribed protocol.  The only effect noted was  an  increase
in lactate dehydrogenase (LDH) during the exposure period,
which nonetheless remained within normal limits.

    Exposure to CFC-11 and CFC-12 has been associated with
the  abusive inhalation of aerosols. Bass (1970) concluded
that  deaths  associated  with abusive  aerosol inhalation
were  probably  caused  by  cardiac  arrhythmia,  possibly
aggravated  by  elevated  levels of  catecholamines due to
stress  or  by  moderate hypercapnia.   This deduction was
subsequently  supported by a variety  of investigators who
found  that  many  chlorofluorocarbons can  sensitize  the
hearts  of  various  mammals to  adrenaline,  resulting in
serious arrhythmias or death (section 8.8).

    There are three possible explanations for deaths among
asthmatics  after using anti-asthmatic drug aerosol formu-
lations   containing  chlorofluorocarbons  as  propellant:
ineffectiveness of the anti-asthmatic drug; drug overdose;
toxicity  of  CFC-11 and  other chlorofluorocarbon propel-
lants. However, the amount of chlorofluorocarbon contained
in  the  inspired aerosols  when  used correctly  for  the
intended  purpose is small  compared to that  used in  the
animal  experiments of Taylor  & Harris (1970b),  or under
conditions  of  severe abuse.   This  is supported  by the
animal  experiments  on  the  dose-dependent  relationship
between  cardiotoxic  effects  of chlorofluorocarbons  and
adrenaline described in section 8.8.1.

9.4.  Health effects associated with stratospheric ozone depletion

    There is undisputed evidence that the atmospheric con-
centrations  of  chlorofluorocarbons deplete  ozone in the
stratosphere.   A  reduction  in ozone  concentration will
result  in  increased  transmission of  solar  ultraviolet
radiation  through  the  stratosphere.   Many  significant
adverse  effects of such an  increase in exposure to  this
radiation have been identified.

    The   information  summarized  below   indicates  that
stratospheric  ozone depletion has the  potential to exert
very substantial effects on human health.

9.4.1.  Skin cancer effects

    One  of the most well-defined human health effects re-
sulting  from stratospheric ozone depletion is an increase
in  the frequency of skin  cancer expected as a  result of
even   small  increases  in  UV-B  radiation  (280-320 nm)
reaching the earth's surface (US EPA, 1987a; Kripke, 1989;
van der Leun, 1988).

    The  most definitive evidence  links the incidence  of
non-melanoma  basal and squamous  cell carcinomas to  UV-B
radiation.   These carcinomas occur most frequently on the
sun-exposed  skin  of  light-skinned Caucasian  people and
their  incidences increase with age. The geographical dis-
tribution  data suggest a relationship to cumulative life-
time  exposure to sunlight  (Urbach, 1969).  Increases  in
skin  cancers during the past  few decades in the  USA are
probably  partly due to increasing exposure to natural and
artificial sources of UV-B radiation and partly to greater
longevity  allowing  for  the appearance  of  such cancers
after long latencies (several decades). Although this long
latency makes it unlikely that the increases  already  ob-
served in skin cancer rates are due to the small decreases
in  stratospheric ozone observed  during the past  decade,
there  is  extensive  evidence for  predictions of further
increases  in basal and squamous cell skin cancer rates if
stratospheric  ozone depletion continues.   Such depletion

will result in greater increases in UV-B radiation near to
280 nm  rather than in the upper end of the affected wave-
length  range (320 nm). Skin cancers are mostly induced by
UV radiation  at around 300 nm, as  demonstrated by exper-
imental animal studies.  Tumour incidence is a function of
the  dose  received regularly  and  the period  over which
doses occur (frequently corresponding to age). There is no
evidence of any threshold. A greater-than-linear growth of
cancer incidence rate can be predicted due to several fac-
tors  including optical amplification and bioamplification
(van der Leun & Daniels, 1975).

    The  optical  amplification factor  indicates the per-
centage  increase in the carcinogenically  effective radi-
ation  caused by a 1%  decrease in total ozone  column. It
depends  on the wavelengths  involved in the  induction of
skin cancer by UV radiation because, when ozone levels de-
crease, the shorter wavelengths in the UV-B range increase
more  steeply than the longer wavelengths. The optical am-
plification also depends on the pathlength of the UV radi-
ation  through the ozone layer. This makes the optical am-
plification to some extent dependent on geographical lati-
tude, i.e. it increases from the equator to the poles.

    The biological amplification factor indicates the per-
centage increase in skin cancer incidence caused by  a  1%
increase  in the carcinogenically effective radiation.  It
is  not directly proportional  to the UV-B  radiation, but
follows  a higher power  of the radiation  (Fears et  al.,

    On  the basis of a recently determined action spectrum
for  UV carcinogenesis in hairless mice (Slaper, 1987), it
can  be calculated using  both amplification factors  that
with a 1% decrease in total ozone column,  effective  UV-B
radiation  will increase by  1.6%, the incidence  of basal
cell carcinomas by 2.7% and of squamous cell carcinomas by
4.6%  (van der Leun, 1989). In many registries, basal cell
carcinomas  and  squamous  cell carcinomas  are still con-
sidered  together, as non-melanoma skin cancers.  For a 1%
depletion  of ozone, the overall incidence of non-melanoma
skin cancer would increase on average by about 3%.  With a
5% decrease in stratospheric ozone, the incidence of basal
cell carcinoma would increase by 14%, squamous cell carci-
noma  by 25%, and non-melanoma  skin cancer in general  by
16%.   The lighter-skinned white populations  of the world
would  be most  affected, with  45 000 new  cases of  non-
melanoma  skin  cancer  per year  (worldwide) following 1%
stratospheric  ozone depletion and 240 000 new cases annu-
ally following 5% ozone depletion (van der Leun, 1989).

    The  full importance of  such numbers is  difficult to
define at present.  Non-melanoma skin cancers, if detected
early, have a very high cure rate.  The current death rate
is  about 1% of  known cases and  reduced exposure  (e.g.,

decreased  everyday  outdoor  activities,  decreased  rec-
reational  sun exposure, use of  more extensive protective
clothing by farmers or other outdoor workers)  could  help
to reduce skin cancer increases due to ozone depletion.

    Sufficient  evidence exists to show that sunlight also
plays  a role  in the  much more  dangerous (often  fatal)
melanoma forms of skin cancer.  A key uncertainty  is  the
extent  to  which  UV-B radiation,  versus  other sunlight
components,  may specifically contribute to  the induction
of cutaneous melanomas.  The lack, until very recently, of
any  viable experimental animal  model in which  to  study
these   light-activated  skin  pigment  cell  cancers  has
impeded  progress.  However, UV-B radiation has been shown
to  increase melanomas in two animal models (Setlow, 1988;
Ley,  1988), and Kripke (1989) has noted that much greater
growth of melanomas occurs when transplanted into the skin
of UV-irradiated animals, suggesting that UV radiation may
not only initiate melanomas but have promoter  effects  as
well.   Thus,  it is  prudent  to consider  melanoma  skin
cancers  among  potential  health effects  of  ozone layer
depletion (US EPA, 1987d).

9.4.2.  Immunotoxic effects

    Another  potential  effect of  stratospheric ozone de-
pletion  is suppression of immune function. UV-B radiation
appears  to modify immune  function in irradiated  mice in
different ways both locally at the point of  skin  irradi-
ation  and systemically.  Locally-induced  effects include
impairment  of  Langerhans  cells and  abnormal endogenous
cancer cells (Kripke, 1989; Stingl et al.,  1983).   After
exposure  to  UV-B  radiation, Langerhans  cells no longer
present antigens to the helper T-lymphocytes. Consequently
when  contact allergens are applied  to UV-B-exposed skin,
no contact allergy ensues. Instead, suppressor lymphocytes
are  activated,  which  prevent any  subsequent immune re-
sponse  to the same antigen. Suppressor T-cell lymphocytes
are  normally  involved  in regulating  the  magnitude and
duration  of immune responses.   Their activation by  UV-B
radiation  prevents  the  development  of  natural  immune
responses  against  UV-B-induced skin  cancers and thereby
contributes to their growth and spread to other  parts  of
the  body (Daynes et al., 1986).  In addition, circulation
of  UV-B-activated  suppressor lymphocytes  throughout the
body,  and an associated reduction  in helper lymphocytes,
results  in  a  general, systemic  suppression  of certain
immune functions. Thus, UV-B-irradiated mice not only fail
to  exhibit contact allergy responses to chemicals applied
to  irradiated skin but they also have impaired ability to
respond  to chemicals applied to  non-irradiated skin.  In
addition,  they have decreased  lymphocyte-mediated immune
responses  to foreign substances  injected under the  skin
(i.e.  delayed hypersensitivity reactions) (Noonan et al.,
1981).  The systemic suppression of immune function due to

UV radiation has been demonstrated to (a) occur in several
animal species, (b) increase as a function  of  increasing
UV-B  dosage, and (c) persist beyond the initial period of
UV exposure  (Giannini, 1986; Howie et  al., 1986; Kripke,
1988).   Two studies of infectious agents showed that UV-B
radiation  resulted in suppressed immune  response in mice
to  Herpes simplex that lasted for several months (Howie et
al.,  1986)  and  that UV-B-irradiated  mice infected with
 Leishmania failed  to exhibit the delayed hypersensitivity
immune  responses that were induced in non-irradiated mice
(Giannini, 1986). However, insufficient evidence exists to
make a quantitative estimation of the dependence of poten-
tial  increases  in the  incidences  of specific  types of
infectious  diseases  in  humans  on  stratospheric  ozone

9.4.3.  Ocular effects

    Adverse occular effects resulting from the exposure to
UV-B  radiation  may also  be  the consequence  of strato-
spheric  ozone  depletion (US  EPA,  1987a; van  der Leun,
1988,1989).   One effect, "snow-blindness", is typically
transient,  lasting  only a  few  days, but  its  possible
increase  at higher (snowier) latitudes is of interest. Of
much  more concern, however,  is evidence that  UV-B radi-
ation  increases cataract formation  (Pitts et al.,  1986)
and  the suggestion that 1%  stratospheric ozone depletion
would increase cataract prevalence by about 0.25  to  0.6%
(roughly  equivalent to about 24 000  to 57 000 more cases
in the USA per year at present population levels) (US EPA,

9.4.4.  Effects on vitamin D synthesis

    Skin  exposure to UV-B radiation  causes the formation
of  vitamin D3.   It  has been suggested  that some  popu-
lation  segments  that  suffer from  vitamin D deficiency,
e.g.,  dark-skinned children in northern  cities, children
in  families with strict macrobiotic diets, elderly people
living mainly indoors (Aaron et al., 1974), and especially
children,  might  gain  some benefit  from  increased UV-B
radiation  resulting  from stratospheric  ozone depletion.
Excess  production of vitamin D3 in  other groups would be
unexpected  since its formation is  self-limiting (Holick,

9.4.5.  Exacerbation of photochemical smog formation and effects

    Increased  UV-B radiation would be expected to facili-
tate  tropospheric ozone formation and acid aerosol forma-
tion,  the latter due  to increased surface  hydrogen per-
oxide  concentrations.  The health effects associated with
both  tropospheric ozone and  acid aerosols would  then be
expected  to occur with greater frequency and severity (US
EPA, 1986; Lippmann, 1989; Grant, 1989).


10.1.  Evaluation of human health risks

10.1.1.  Direct health effects resulting from exposure to fully halogenated

    The kinetics and metabolism of chlorofluorocarbons are
characterized  by  rapid pulmonary  absorption and distri-
bution.  There is no indication of any accumulation. Meta-
bolic transformation of the chlorofluorocarbons considered
in  this monograph  is negligible,  if it  occurs at  all.
Therefore, toxic effects of metabolites are very unlikely.
The  acute toxicity of chlorofluorocarbons is very low, as
demonstrated in studies on various animal species  and  by
different routes of administration. It is characterized by
effects   on  the  heart,  the   respiratory  system,  and
occasionally the liver. The effects are in accordance with
the  symptomatology  observed  in acute  intoxications  in

    After  repeated exposure, comparable clinical symptoms
can be observed. Alterations in the liver and kidney occur
occasionally. In humans, CNS, cardiovascular and respirat-
ory  symptoms occur in cases of severe abuse and in uncon-
trolled  or accidental occupational exposure.   Under con-
ditions  of use involving  short-term exposures of  up  to
1000 ppm, no adverse health effects would be expected.

    An  evaluation of the animal studies indicates no car-
cinogenic risk to human beings.  This is underlined by the
fact  that the chlorofluorocarbons discussed in this mono-
graph  are devoid of  genotoxicity in different  mutagenic
end-points  and cell transformation.  In  a limited cohort
study  with 539 exposed workers, neither  increased deaths
nor increased tumour ratios were reported.  Studies on the
influence   of  reproduction  (fertility,  embryotoxicity,
fetotoxicity,  teratology) and general effects on develop-
mental processes in experimental animals were consistently
negative.  Effects on human reproduction, including intra-
uterine   and   post-natal  development,   have  not  been

    Mean  concentrations in the ambient  air in urban/sub-
urban  areas of 3.4 µg/m3 for   CFC-11 and 6 µg/m3     for
CFC-12  have  been  measured. In  remote/rural  areas, the
corresponding  levels  were  1.0 µg/m3 for     CFC-11  and
1.6 µg/m3 for CFC-12.

    These  exposure  levels  are considered  negligible in
comparison with the concentrations of 25 000 to 50 000 µg/m3
(~5000   to 10 000 ppm) that cause initial signs either of
functional or morphological changes in laboratory animals.
They  are particularly negligible  in comparison with  the
very high exposure levels that cause functional changes in

10.1.2.  Health effects expected from reduction of stratospheric ozone by 

    During  the last decade,  increasing concern has  been
focused on the consequences of a reduction of ozone in the
upper  atmosphere, with the  concomitant increase of  UV-B
radiation  at the surface of the earth. Model calculations
predict,  for  the  next  50 years,  ozone  depletions  of
between  1 and 10%, depending on the scenario used for the
release of chlorofluorocarbons and other trace gases.

    Among  the effects on  human health, the  induction of
non-melanoma  skin  cancer  has been  investigated  exten-
sively,  both in human  epidemiology and in  animal exper-
imental  work.  It is a generally accepted conclusion that
the incidence of non-melanoma skin cancer will increase as
a result of ozone depletion. An estimation based on recent
data predicts that a decrease of atmospheric ozone  by  1%
would lead to an increase in the incidence of non-melanoma
skin cancers by 3%. An ozone depletion by 5% would lead to
an increase of the incidence by 16%.  This latter increase
would   mean  a  worldwide   increase  of  about   240 000
additional  new patients with non-melanoma skin cancer per
year, predominantly light skinned people.

    Indications  are  increasing that  UV-B radiation also
plays  a role  in the  induction and  growth of  cutaneous
melanomas, a more dangerous type of skin  cancer.   Uncer-
tainty, however, especially with regard to the dose-effect
relationship,  makes quantitative predictions  very diffi-
cult. The possibility of an increase in cutaneous melanoma
should therefore be taken into consideration.

    The  immune  system  of experimental  animals  is sup-
pressed in specific ways by UV-B radiation.  This  results
in   a  decreased  resistance  to  implanted  UV-B-induced
tumours and an increased growth of such tumours  in  mice,
in  the suppression of sensitization by contact allergens,
and the response to allergens in sensitized  animals.   It
also  results  in the  impairment  of the  immune response
against  certain infectious agents;  this has been  demon-
strated  for  Herpes simplex and  Leishmania sp.  There  are
indications  that  similar  suppression of  the immune re-
sponse by UV-B radiation may occur in humans. The antigen-
presenting  Langerhans cells in  the skin are  damaged and
allergic responses are depressed.  Although much still has
to  be learned through  further research, the  possibility
that  immune suppression effects and a consequent increase
in the incidence of some infectious diseases  might  occur
as a result of stratospheric ozone depletion should not be

    There  are  indications that  UV-B radiation increases
cataract   formation,  an  important  cause  of  blindness
especially in areas with limited medical facilities.

10.2.  Effects on the environment

    Other  than  the theory  that chlorofluorocarbons con-
tribute to the "greenhouse" effect, there is no evidence
available  of other direct ecological  effects produced by
the chlorofluorocarbons discussed in this monograph.

    Studies  addressing the effects  of UV-B radiation  on
plants have concentrated on crop plants and  have  usually
been  conducted  at temperate  latitudes.  This represents
only a small portion of the major ecosystems of the world.
Although  there are many uncertainties  resulting from the
complexities  of the experiments,  the data now  available
suggest  that  crop  yields are  potentially vulnerable to
increased levels of solar UV-B radiation. Out of more than
200 species and cultivars screened for UV tolerance, about
two-thirds  have been found to be sensitive. The most sen-
sitive  plant  groups include  crops  related to  peas and
beans, melons, mustard, and cabbage.  Members of the grass
family are generally less sensitive.

    Experimental  evidence  indicates  that there  is some
degree  of tolerance to UV-B  radiation in the gene  pool.
This  is based on the  high degree of variation  in sensi-
tivity  to UV radiation among crop cultivars.  The genetic
basis for the sensitivity has yet to be determined.

    The effect of enhanced levels of UV-B radiation on the
quality  of crops has  been studied. The  protein and  oil
content  of  selected  cultivars  of  soybean  seeds  were
reduced by up to 10% when plants were exposed to UV levels
simulating a 25% ozone depletion.

    Studies  regarding  the  effects of  UV-B radiation on
forest  productivity are limited.  There  are results only
for  seedlings, and they are for levels of exposure equiv-
alent  to a 40% ozone  reduction.  These studies showed  a
reduction  in  growth  and  photosynthesis  following  the
exposure of loblolly pine seedlings. There is experimental
evidence  that increased UV-B  radiation levels can  cause
shifts in community structure.

    Exposure  to UV-B radiation  has been shown  to affect
both  plant  and  animal components  of marine ecosystems.
These effects include decreases in fecundity, growth, sur-
vival, and other parameters.

10.3.  Conclusions

    The available toxicological data on the fully halogen-
ated chlorofluorocarbons reviewed in this monograph show a
low acute and chronic toxicity and indicate  no  mutagenic
or  carcinogenic  potential.   The human  health risks are
mainly  confined  to  occasional high  exposures  that may

occur  when handling these  substances.  In contrast,  the
indirect  effects on human beings from the accumulation of
these  substances in the stratosphere may lead to substan-
tial  effects on human health, mainly due to the depletion
of stratospheric ozone resulting in an increase in effects
from UV-B radiation. The projected increase in  the  inci-
dence of non-melanoma skin cancers, a possible increase in
melanoma  skin cancers, and immunotoxic and ocular effects
all  lead to the  conclusion that immediate  and effective
international  cooperation is necessary to  reduce further
stratospheric ozone depletion.


1.  The  toxicity data base for  some chlorofluorocarbons,
especially  those  containing hydrogen,  is inadequate for
quantitative  risk assessment.  Additional  information on
the chronic toxicity, carcinogenicity, and teratogenicity/
reproductive  effects  of  these compounds,  especially by
inhalation exposure, is needed.

2.  An assessment of the effects of increased  UV-B  radi-
ation is summarized in Table 16.

Table 16.  Potential effects of increased UV-B radiation 
resulting from decreased stratospheric ozonea
Effects           State of knowledge   Potential global impact
Skin cancer       Moderate to high     Moderate
Immune system     Low                  High
Cataracts         Moderate             Lowb
Plant lifec       Low                  High
Aquatic lifec     Low                  High
Climate impactsd  Moderate             Moderate
Ambient ozone     Moderate             Lowe
a  Modified from SAB-EC-87-025  Review of EPA's Assessment of the Risks 
    of Stratospheric Modification by the Stratospheric Ozone 
   Subcommittee, Science Advisory Board, US Environmental Protection 
   Agency, March, 1987. 
b  A more recent consideration of the influence of ozone depletion on 
   the incidence of catar-acts suggests that the impact in this respect 
   may be more serious (US EPA, Assessing the Risks of Trace Gases that 
   can modify the Stratosphere, Chapter 10, December 1987). 
c  See section 6.
d  Contribution of both stratospheric ozone depletion itself and gases 
   causing such depletion to climatic changes, including sea level rise. 
e  Impact could be high in selected urban or rural areas typified by 
   local or regional scale surface-level ozone air pollution problems. 

    More research is needed in those areas where knowledge
is lacking and the potential global impact is high.  These
include  the  following  eight specific  areas  of  future
research  and assessment that are especially important for
understanding   and   dealing  with   stratospheric  ozone
depletion effects on human health:

*   the  investigation of mechanisms  of immunosuppression
    in animal models and humans;

*   the identification of infectious diseases that include
    a  stage or process that could be worsened by exposure
    to  UV-B radiation, and  the development of  models to
    explain these diseases;

*   the  investigation  of  wavelength dependence  and the
    development  of  dose-response information  for humans
    concerning the effects of UV-B exposure on  the  inci-
    dence of infectious diseases;

*   the  determination  of  the impact  of UV-B immunosup-
    pression on vaccination efficacy;

*   the clarification of the role of immunological changes
    in  the induction of  melanomas and non-melanoma  skin
    cancers by UV radiation;

*   the  determination  of  the action  spectra  and dose-
    effect  relationships for the induction of the various
    types of melanoma by UV radiation;

*   the establishment of a better definition of the action
    spectra  for the induction of squamous cell carcinoma,
    and especially basal cell carcinoma, by UV radiation;

*   the  investigation of the biology  and epidemiology of
    cataracts,  and of methods to  reduce the risk of  eye

3.  The  use of CFC-11 and  CFC-12 as propellants for  the
disinsection of aircraft by aerosol sprays is  still  rec-
ommended  by some authorities.  There is urgent need for a
new non-ozone-depleting, non-flammable, safe, non-irritant
propellant for this use, since the older  propellants  are
already banned in many countries.

4.  Effective  international  cooperation is  necessary to
reduce  future stratospheric ozone depletion, and for this
purpose cuts in the emission of ozone-depleting chloroflu-
orocarbons  of at least  80-90% are necessary.   The first
priority is to find substitutes and the second  to  devise
adequate disposal procedures for existing waste chloroflu-
orocarbons.   It  is  recommended that  all countries take
steps to reduce the use of chlorofluorocarbons  with  high
stratospheric ozone-depletion potential.


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1. Identité, propriétés physiques et chimiques, méthodes d'analyse

    La  présente monographie ne traite que des chlorofluo-
rocarbures  (CFC) obtenus par substitution  de la totalité
des atomes d'hydrogène du méthane et de l'éthane  par  des
atomes  de fluor et de chlore.  Nombre de ces composés ont
un  intérêt commercial et certains d'entre eux contribuent
à  la  diminution  de  la  couche  d'ozone.   Les composés
examinés dans ce qui suit sont les suivants: le trichloro-
fluorométhane  (CFC-11),  le  dichlorofluorométhane  (CFC-
12), le chlorotrifluorométhane (CFC-13), le difluoro-1,2-tétra-
chloro-1,1,2,2-éthane  (CFC-112), le difluoro-1,1-tétrachloro-
1,2,2,2-éthane (CFC-112a), le trichloro-1,1,2-trifluoro-1,2,2-
éthane (CFC-113), le  trichloro-1,1,1-trifluoro-2,2,2-éthane
(CFC-113a), le dichloro-1,1,2,2-tétrafluoro-1,1,2,2-éthane
(CFC-114), le dichloro-1,1-tétrafluoro-1,2,2,2-éthane (CFC-
114a) et le chloro-1-pentafluoro-1,1,2,2,2-éthane (CFC-115).
Les  composés qui ne contiennent  pas de chlore (comme  le
CFC-134a et le CFC-116) ne sont pas examinés.   Quant  aux
composés  qui contiennent de l'hydrogène (comme le chloro-
difluorométhane),   ils   feront   l'objet  d'un   rapport

    Les  chlorofluorocarbures  du commerce  comptent parmi
les  produits  organiques  les  plus  purs  qu'on   puisse
obtenir.   Ils se caractérisent en général par une tension
de  vapeur et une densité  élevées ainsi que par  une vis-
cosité, une tension superficielle, un indice de réfraction
et  une solubilité dans l'eau faibles. Le degré de substi-
tution  par  le  fluor modifie  fortement  les  propriétés
physiques  et  en  général  à  mesure  qu'il  augmente, la
tension  de vapeur augmente  et le point  d'ébulition,  la
densité et la solubilité dans l'eau diminuent.

    Les  chlorofluorocarbures  examinés  dans la  présente
monographie   sont  assez  stables  chimiquement   et,  en
l'absence  de catalyseur métallique, leur vitesse d'hydro-
lyse  est faible.  Ils  sont très résistants  aux oxydants
classiques  aux  températures  inférieures à  200 °C.   En
général,  les  chlorofluorocarbures présentent  une grande
stabilité  thermique et sont  extrêmement résistants à  la
presque  totalité  des  agents chimiques.   Toutefois  ils
réagissent  violemment sur les métaux  de forte réactivité

    Plusieurs  méthodes d'analyse sont utilisables pour le
dosage  des chlorofluorocarbures dans divers  milieux.  Il
s'agit  de la spectrophotométrie, de la chromatographie en
phase gazeuse avec plusieurs variantes et de  la  spectro-
métrie  de masse.  Dans la  plupart des cas on  utilise la
chromatographie  en phase gazeuse avec différents modes de
détection;  dans  ce cas,  les  limites de  détection sont

généralement  de l'ordre d'une partie  par trillion (ppt).
Les  méthodes  de  prélèvement des  échantillons  ont  été
modifiées  pour obtenir une sélectivité et une sensibilité

2.  Sources d'exposition humaine et environnementales

    Les  chlorofluorocarbures  étudiés  dans  la  présente
monographie  n'existent pas à l'état  naturel mais presque
tous,  sauf  ceux  qui sont  utilisés comme intermédiaires
chimiques, sont libérés dans l'environnement.  En 1985, on
estime que la production mondiale des chlorofluorocarbures
les  plus importants susceptibles de provoquer une diminu-
tion  de la couche d'ozone (CFC-11, CFC-12, CFC-113) était
d'au  moins un million de tonnes.  La production n'est pas
limitée  aux  grands  pays industriels  puisqu'au moins 16
pays  en fabriquent.  La  mise en oeuvre  du Protocole  de
Montréal  va probablement provoquer un  renversement de la
tendance  actuelle qui est  à l'accroissement de  la  pro-

    La  méthode la plus importante pour la préparation des
principaux  chlorofluorocarbures consiste dans le déplace-
ment catalytique du chlore des chlorocarbures par le fluor
en  présence de gaz fluorhydrique anhydre.  La plupart des
émissions  dans l'environnement se  produisent lors de  la
mise  au  rebut de  matériel  de réfrigération  plutôt que
pendant  la fabrication, le stockage ou la manipulation de
ces  produits.   Les restrictions  imposées  par la  loi à
l'utilisation  de ces produits  dans de nombreux  pays ont
réduit  la libération dans l'atmosphère  des chlorofluoro-
carbures   utilisés  comme  gaz  propulseurs;   quant  aux
émissions  d'agents de soufflage, elles  sont faibles.  En
raison  de la forte tension de vapeur de ces produits à la
température  ambiante, presque toute la masse libérée dans
l'environnement  finit par s'accumuler  dans l'atmosphère.
On  estime qu'en 1985  les émissions annuelles  totales de
chlorofluorocarbures,  principalement  du  CFC-11  et   du
CFC-12,  atteignaient  environ  un million  de tonnes, les
émissions  cumulées  de ces  produits  entre 1931  et 1985
s'élevant à environ 13,5 millions de tonnes.

    En  1985, les différentes  utilisations dans le  monde
des  chlorofluorocarbures  se  décomposaient  comme  suit:
réfrigérants 15%, agents de soufflage 35%, gaz propulseurs
pour  aérosols  31%,  divers 7%,  sans utilisation définie
12%.  Aux Etats-Unis d'Amérique, la  proportion de chloro-
fluorocarbures   utilisés  comme  gaz   propulseurs  était
beaucoup plus faible en raison des restrictions imposées à
leur utilisation.

3.  Transport, distibution et transformation dans l'environnment

    Les  chlorofluorocarbures du commerce  persistent dans
l'environnement  en raison de leur stabilité chimique.  La

durée moyenne de persistence dans l'atmosphère est estimée
à  65,  110, 400,  90, 180 et  380 ans pour le  CFC-11, le
CFC-12,  le CFC-13, le CFC-113,  le CFC-114 et le  CFC-115
respectivement.   Cette  longue  persistance  permet   une
diffusion dans la stratosphère où les chlorofluorocarbures
donnent naissance par voie photochimique à des  atomes  de
chlore qui réagissent sur la couche d'ozone. En outre, ces
composés contribuent à l'effet de serre.

4.  Niveaux dans l'environnement et exposition humaine

    Plusieurs  chercheurs ont fait état de la distribution
mondiale  des chlorofluorocarbures.  Des  mesures récentes
portant  sur la variation en fonction de la latitude de la
concentration en chlorofluorocarbures ont montré qu'il n'y
a  guère de différence entre l'hémisphère nord et l'hémis-
phère  sud pour ce  qui concerne le  CFC-11 et le  CFC-12.
Il  n'y a  également guère  de variations  en fonction  de
l'altitude jusqu'à 6 km au-dessus de la surface terrestre.
Les concentrations mesurées dans l'air des villes  et  des
banlieues  sont plus élevées que celles qu'on observe dans
les  régions  rurales  ou écartées  en  raison d'émissions

    Les  concentrations atmosphériques de CFC-11 et CFC-12
ont  augmenté régulièrement jusqu'en 1985 où leurs concen-
trations  globales aux Etats-Unis  d'Amérique atteignaient
9120 ng/m3    dans les zones  urbaines et suburbaines,  et
2720 ng/m3   dans les zones rurales ou écartées.  A partir
de  ces données, on  estime que l'exposition  humaine  par
inhalation  dans ces deux  types de secteur  s'établissait
respectivement à 182 et 54 mg/jour.

    A la surface des océans, la concentration  moyenne  de
CFC-11 et de CFC-12 mesurée dans trois  secteurs  éloignés
s'est  révelée de l'ordre de 0,2 ng/litre.  Toutefois on a
mesuré  des concentrations de 0,62 ng de CFC-11/litre dans
la  Mer du  Groenland en  1982 et  des valeurs  atteignant
0,54 ng/litre  ont été observées dans les eaux côtières du
Japon. En ce qui concerne le CFC-12, la plus forte concen-
tration dans ces mêmes eaux était de  0,33 ng/litre.   Des
valeurs  beaucoup plus élevées  ont été obtenues  dans les
eaux  douces  du Lac  Ontario où on  a mesuré des  concen-
trations  de 249 mg de  CFC-11 par litre  et de 572 ng  de
CFC-12  par litre. On  n'a pas décelé  de chlorofluorocar-
bures dans l'eau de boisson mais ils étaient présents dans
la  neige et dans  l'eau de pluie  en Alaska, dans  le Lac
Ontario  et dans le Niagara.  Du CFC-11 a été décelé à des
concentrations  de 0,1 à 5 µg/kg   de poids à sec (parties
par milliard) dans divers organes de poissons et  de  mol-
lusques.  Toutefois  la  présence de  chlorofluorocarbures
dans les préparations alimentaires n'est pas attestée.

5.  Cinétique et métabolisme

    Des   chlorofluorocarbures   peuvent   pénétrer   dans
l'organisme  humain  par inhalation,  ingestion ou contact
cutané.  C'est l'inhalation qui constitue la voie de péné-
tration la plus fréquente et la plus importante,  la  voie
d'élimination  principale étant l'air exhalé.   Des études
contrôlées sur des volontaires et des animaux d'expérience
ont  fourni des données substantielles relatives à l'expo-
sition  à un certain nombre  de chlorofluorocarbures.  Ces
données montrent que les chlorofluorocarbures:

*   peuvent  être absorbés au niveau de la membrane alvéo-
    laire, des voies digestives ou de la peau;

*   passent rapidement dans le sang après inhalation;

*   passent dans le sang d'autant moins vite que leur con-
    centration y est plus élevée;

*   une fois dans le sang, sont absorbés par  divers  tis-

*   finissent  par  atteindre  une concentration  sanguine
    stationnaire  au  bout  d'une durée  d'exposition suf-
    fisante,  ce  qui  indique qu'un  équilibre  s'établit
    entre  l'air  chargé  de  chlorofluorocarbures  et  le

*   continuent  à  être  absorbés  par  les  tissus  après
    stabilisation du taux sanguin initial et continuent de
    pénétrer dans l'organisme.

    L'expérimentation animale montre que les chlorofluoro-
carbures sont rapidement absorbés après inhalation et sont
amenés par le sang à la presque totalité des tissus. C'est
dans les tissus adipeux ou lipidiques qu'ils atteignent en
général les concentrations les plus élevées.  Toutefois on
trouve également des chlorofluorocarbures dans les organes
bien  irrigués comme le coeur,  les poumons, les reins  et
les muscles.

    Les  résultats fournis par des études métaboliques sur
l'animal  et sur l'homme montrent que les chlorofluorocar-
bures  résistent à la  dégradation ou à  la métabolisation
par  les systèmes biologiques.  En fait, après exposition,
les chlorofluorocarbures sont généralement très peu ou pas
du tout métabolisés.

    Quelle  que soit la  voie de pénétration,  les chloro-
fluorocarbures  sont  éliminés presque  exclusivement dans
l'air   expiré.    Lors   d'études  visant   à  rechercher
d'éventuels  produits  de transformation  métabolique dans
les  urines ou les matières  fécales, on n'a pas  récupéré
ces produits ou leurs métabolites en quantités notables.

6.  Effets sur l'environnement

    Certains  chlorofluorocarbures, notamment les  CFC-11,
12, 113, 114 et 115 sont extrêmement stables dans les con-
ditions  qui règnent dans  la basse atmosphère.  Ce  n'est
qu'après  être  parvenus  dans la  haute atmosphère qu'ils
perdent des atomes de chlore par photolyse sous l'influen-
ce  des  rayonnements de  haute  énergie qui  y pénètrent.
Ces  radicaux chlore provoquent la destruction catalytique
de  l'ozone.  L'ozone stratosphérique  absorbe le rayonne-
ment  ultra-violet solaire (UV-B de 280-320 nm de longueur
d'onde), de sorte que seule une partie de  ce  rayonnement
parvient jusqu'à la surface de la terre.

    L'expérience  montre qu'un acroissement du rayonnement
UV-B à la surface de la terre par suite de  la  diminution
de la couche d'ozone aurait des effets délétères  sur  les
organismes  terrestres et aquatiques. Malgré  les incerti-
tudes tenant à la complexité de l'expérimentation  sur  le
terrain, les données disponibles montrent que le rendement
des  récoltes  et la  productivité  des forêts  auraient à
souffrir  d'un accroissement du rayonnement  UV-B solaire.
Il  semble également que l'accroissement de ce rayonnement
puisse modifier la répartition et l'abondance des végétaux
ainsi que la structure de l'écosystème.

    Différentes  études portant sur des écosystèmes marins
ont montré que le rayonnement UV-B pouvait être nocif pour
les  larves de  poissons et  les alevins,  les  larves  de
crevettes  et  de  crabes,  les  copépodes  ainsi  que les
végétaux  qui sont essentiels au réseau alimentaire marin.
Parmi ces effets nocifs, on peut citer une réduction de la
fécondité, de la croissance et de la survie.  L'expérience
montre que même une faible augmentation de l'exposition au
rayonnement  UV-B  ambiant pourrait  entraîner une modifi-
cation sensible de l'écosystème.

7.  Effets sur les animaux d'expérience et les systèmes  in vitro

    On  a largement étudié  la toxicité aiguë  des chloro-
fluorocarbures  après inhalation.  Ceux qui sont envisagés
dans  la  présente  monographie sont  faiblement  toxiques
lorsqu'ils sont inhalés.  Les symptômes d'une intoxication
aiguë  comportent  des  effets  sur  le  système   nerveux
central,  des  effets cardiovasculaires  secondaires ainsi
qu'une  irritation  des  voies respiratoires.   Le  peu de
données  dont on dispose au sujet de la toxicité aiguë par
voie  orale des chlorofluorocarbures montrent que celle-ci
est   faible.  Appliqués sur  la peau à  hautes doses,  le
CFC-112,  le CFC-112a et  le CFC-113 provoquent  une irri-
tation  d'intensité  variable  mais  pas  d'autres  effets

    Des  études  d'inhalation  de  courte  durée  ont  été
effectuées sur le CFC-11, le CFC-12, le CFC-112,  le  CFC-
113,  le CFC-114 et  le CFC-115.  Les  résultats indiquent
que la toxicité est faible, les effets observés s'exerçant
principalement  au niveau du système  nerveux central, des
voies respiratoires et du foie. Les études de toxicité par
voie orale confirment la faible toxicité de ces produits.

    Lors d'une étude d'inhalation à long terme,  des  rats
ont  été exposés à du  CFC-113 aux doses de  0,2, 1 ou  2%
(15,3, 76,6 ou 183 g/m3)   six heures par jour, cinq jours
par  semaine pendant des périodes allant jusqu'à deux ans.
Aucune  anomalie n'a été observée,  ni sur le plan  histo-
logique ni en ce qui concerne les résultats  des  analyses
biologiques. La seule anomalie que les auteurs ont imputée
à  ce traitement était une réduction du gain de poids cor-
porel  chez les groupes  exposés aux deux  doses les  plus

    Les  données disponibles indiquent que les chlorofluo-
rocarbures   complètement   halogénés  examinés   dans  la
présente monographie ont une activité mutagène ou cancéro-
gène  faible ou nulle.  A cet égard des résultats négatifs
ont été obtenus in vitro sur des bactéries et des cellules
mammaliennes   avec   ou   sans  activation   métabolique.
L'épreuve  de  létalité  dominante a  également  donné des
résultats négatifs.

    Des études de cancérogénicité à long terme  (par  voie
orale et par inhalation) effectuées avec du CFC-11  et  du
CFC-12  sur des souris et des rats ont donné des résultats
négatifs.   Chez  les  rats,  on  a  observé  une réaction
tumorigène  au niveau de la cavité nasale après inhalation
de  CFC-113 mais cette réaction a été jugée douteuse.  Les
tumeurs   présentaient  une  morphologie   diversifiée  et
l'incidence  n'était  pas  liée  à  la  dose.   Bien qu'on
utilise des chlorofluorocarbures depuis plus de 50 ans, il
n'existe  qu'une seule étude de  cohorte (539 travailleurs
exposés).  Elle n'a pas  révélé d'augmentation de  la mor-
talité globale ni de la mortalité par cancer.

    Sur  les  huit  chlorofluorocarbures examinés  dans le
présent document, seuls le CFC-11, le CFC-12 et le CFC-113
ont fait l'objet d'études de toxicité sur le développement
publiées  dans la littérature scientifique. Il n'existe de
preuve  d'embryotoxicité,  de foetotoxicité  ou de térato-
génicité pour aucun de ces trois produits.

8.  Effets sur l'homme

    Des études contrôlées sur des volontaires à  qui  l'on
avait administré du CFC-11 et du CFC-12 n'ont  pas  révélé
d'effets  observables sur les paramètres hématologiques et
biochimiques,  le tracé électrocardiographique et électro-
encéphalographique,  la  fonction pulmonaire  ni les para-
mètres neurologiques.

    A  forte  concentration,  les sujets  ont ressenti des
picotements  et  des  bourdonnements d'oreille  et ils ont
éprouvé de l'appréhension.  On a noté des modifications du
tracé  électroencéphalographique  en  même temps  que  des
difficultés  d'élocution et une réduction des performances
dans  les tests psychologiques. L'exposition à une concen-
tration de 11% (545 g/m3)   de CFC-12 pendant   11 minutesa
a  provoqué  une  arythmie cardiaque  notable suivie d'une
baisse du niveau de conscience et d'une amnésie au bout de
10 minutes.

    Aprés  exposition à du CFC-12 à la concentration de 1%
(50 g/m3)    pendant 150 minutes, on a  observé une réduc-
tion  de 7% dans les  résultats d'épreuves psychomotrices,
en  revanche aucun effet  n'a été noté  à la dose  de 0,1%
(5 g/m3).

    Dans  une étude au cours de laquelle 10 sujets ont été
exposés à du CFC-11, du CFC-12, du CFC-14,  deux  mélanges
de  CFC-11 et de CFC-12 et ainsi qu'à un mélange de CFC-12
et de CFC-114 (concentrations dans l'air inspiré comprises
entre 16 et 150 gr/m3)   pendant 15, 45 ou 60 secondes, on
a  observé une réduction  sensible de la  capacité  venti-
latoire  pulmonaire (FEF50, FEF25) dans  chaque cas, ainsi
qu'une  bradycardie,  une  irrégularité accrue  du  rythme
cardiaque et un bloc auriculo-ventriculaire.

    Après   exposition  à  des  concentrations   de  0,15%
(12 g/m3),   0,25% (19 g/m3),   0,35% (27 g/m3)   et 0,45%
(35 g/m3)   de CFC-113 pendant 165 minutes, on a procédé à
l'évaluation des performances psychomotrices.  Aucun effet
n'a  été constaté à  la concentration la  plus faible;  en
revanche,  les  sujets  éprouvaient une  difficulté  à  se
concentrer et les résultats des tests ont été un peu moins
bons à partir de 0,35% (27 g/m3).

    D'après  des études de  portée limitée, il  semblerait
que  les sujets ayant  déjà eu des  réactions  allergiques
cutanées  aux déodorants en aérosol contenant du CFC-11 ou
du  CFC-12, puissent être sensibilisés  à des applications
cutanées de certains chlorofluorocarbures.  Chez cinq non-
fumeurs,  l'exposition  à du  CFC-11  n'a pas  perturbé la
fonction muco-ciliaire trachéenne.

    D'après  deux études, il semblerait  qu'une exposition
professionnelle  normale  au  CFC-113  ne  comporte  aucun
risque sérieux pour la santé.  Aucun effet indésirable n'a
été  noté à des  taux d'exposition professionnelle  attei-
gnant  0,47   (36,7 g/m3),    le taux  moyen  d'exposition
étant de 0,07% (5,4 g/m3).
a   Tout au long de la présente monographie, les pourcentages de 
    chlorofluorocarbures dans l'air sont exprimés au moyen du quotient du 
    volume de chlorofluorocarbures par le volume d'air.

    Plusieurs   études  ont  fait  état  d'une  diminution
importante  de la capacité ventilatoire chez des coiffeurs
qui  utilisaient des bombes aérosol  contenant des chloro-
fluorocarbures.   On  a  signalé des  effets neurologiques
après  exposition  professionnelle à  des chlorofluorocar-
bures.  C'est ainsi qu'on a décrit un cas  de  neuropathie
chez  un employé d'une  blanchisserie exposé à  du  tétra-
chloroéthylène  et  à des  concentrations indéterminées de
CFC-113 pendant six ans.

    Des  cas d'exposition non-professionnelle accidentelle
ou  abusive  consécutive  à l'inhalation  d'aérosols  sont
également  attestés,  les  principaux symptômes  étant une
dépression  du  système  nerveux  central  et  des  effets
cardiovasculaires.  Ces  réactions  indésirables,  suscep-
tibles  parfois de conduire à  la mort, sont attribuées  à
une  arythmie  cardiaque  éventuellement aggravée  par une
élévation  des catécholamines imputables au  stress ou par
une hypercapnie modérée.

    L'accroissement  du rayonnement UV-B devrait entraîner
des  effets essentiellement nocifs  pour la santé  humaine
mais  notre  connaissance de  ces  divers effets  est très
variable.  Pratiquement  personne ne  conteste que l'inci-
dence  des cancers cutanés  non-mélanomateux augmenterait.
Des  projections basées sur des  données récentes montrent
que l'incidence de ces cancers augmenterait de 3% pour une
diminution de 1% de la couche d'ozone.  Il s'ensuit qu'une
diminution  de 5% de la couche d'ozone entraînerait chaque
année  dans  le  monde,  au  bout  de  quelques décennies,
200 000 cas supplémentaires de cancers cutanés non mélano-

    Le  rayonnement UV-B joue  également un rôle  dans  la
formation  des  mélanomes  cutanés qui  sont  encore  plus
dangereux.   Toutefois on n'est  pas encore en  mesure  de
dégager des relations dose-réponse précises.

    Le  rayonnement UV-B peut influer de diverses manières
sur le système immunitaire.  Bien que, faute  de  connais-
sances  suffisantes, on ne  soit pas encore  en mesure  de
prévoir quelles seraient exactement les conséquences d'une
réduction de la couche d'ozone pour la santé  humaine,  il
est  probable  qu'il  s'en suivrait  une  augmentation  de
l'incidence  des  maladies  infectieuses.   Au  niveau  de
l'oeil,  l'effet le plus important serait un accroissement
de  l'incidence  des cataractes,  une opacification perma-
nente du cristallin qui, même au niveau actuel de rayonne-
ment  UV-B, entraîne chez un grand nombre de personnes une
réduction de l'acuité visuelle, voire la cécité.

    En  outre, l'accroissement du rayonnement ultra-violet
favoriserait  la formation du  smog photochimique, ce  qui
aggraverait  encore les problèmes  de santé qui  lui  sont
liés  dans les agglomérations urbaines et les zones indus-

9.  Evaluation des risques pour la santé humaine

    Les  effets directs les  plus importants pour  l'homme
d'une  exposition  à des  chlorofluorocarbures proviennent
des  concentrations  excessives qui  résultent d'accidents
survenus dans l'industrie ou d'une utilisation défectueuse
ou abusive de ces produits comme solvants ou  gaz  propul-
seurs.    La   libération  de   chlorofluorocarbures  dans
l'environnement  général lors du  rejet de déchets  ou  au
cours  du transport et du  stockage est une source  crois-
sante  de préoccupation en raison des conséquences que ces
émissions  incontrôlées pourraient avoir pour  l'avenir de


1.  Evaluation des risques pour la santé humaine

1.1  Effets directs sur la santé résultant d'une exposition à des
chlorofluorocarbures complètement halogénés

    La  cinétique  et le  métabolisme des chlorofluorocar-
bures  se caractérisent par  une résorption pulmonaire  et
une distribution rapides.  Rien n'indique qu'il y  ait  la
moindre  accumulation.  Les chlorofluorocarbures  examinés
dans la présente monographie ne subissent qu'une métaboli-
sation négligeable, si tant est qu'elle se  produise.   En
conséquence,  les effets toxiques  d'éventuels métabolites
sont  très improbables.  Les chlorofluorocarbures  ont une
très  faible toxicité aiguë  comme le montrent  les études
effectuées  sur diverses espèces animales  et par diverses
voies d'administration.  Cette toxicité se caractérise par
des effets sur le myocarde, sur le système respiratoire et
occasionnellement,  sur le foie.  Ces effets correspondent
à  la symptomatologie observée lors d'intoxications aiguës
chez l'homme.

    Des  expositions  répétées conduisent  à des symptômes
cliniques  comparables.  On observe parfois  des anomalies
au  niveau du foie et des reins.  Chez l'homme, un sérieux
abus  de ces substances  ou une exposition  incontrôlée ou
accidentelle  d'origine professionnelle peuvent conduire à
des symptômes neurologiques centraux, cardiovasculaires et
respiratoires.  Dans  des  conditions d'emploi  où l'expo-
sition,  de brève durée,  ne dépasse pas  1000 ppm, il  ne
devrait  pas  se  produire d'effets  indésirables  sur  la

    D'aprés  les études effectuées sur l'animal, on estime
qu'il  n'existe  pas  de risque  cancérogène pour l'homme.
Cette  conclusion  est  corroborée  par  le  fait  que les
chlorofluorocarbures  étudiés dans la présente monographie
sont dépourvus de génotoxicité ainsi que le montre l'étude
des différents paramètres de la mutagénèse et de la trans-
formation cellulaire.  Lors d'une étude de cohorte limitée
à 539 travailleurs exposés, on n'a pas constaté d'accrois-
sement  de la mortalité ni  de la proportion des  tumeurs.
Des  études portant sur l'influence de ces produits sur la
fonction   de  reproduction  (fécondité,   embryotoxicité,
feototoxicité,  tératogénicité) et sur les  effets exercés
au  niveau  du développement  en  général, ont  donné  des
résultats  systématiquement négatifs.  On n'a pas connais-
sance  d'effets  sur  la reproduction  humaine,  notamment
pendant  la vie intra-utérine ou au cours du développement

    On a observé dans l'air ambiant de zones  urbaines  ou
suburbaines  des  concentrations  moyennes de  l'ordre  de
3,4 µg/m3 pour   ce qui concerne le CFC-11 et de 6    µg/m3

pour le CFC-12.  Dans les régions rurales ou écartées, les
valeurs  correspondantes  se  situaient pour  le  CFC-11 à
1,0 µg/m3 et pour le CFC-112 à 1,6 µg/m3.

    Ces  taux d'exposition sont considérés comme négligea-
bles   par   rapport   aux  concentrations   de  25 000  à
50 000 µg/m3      (équivalents à 5000 à 10 000 ppm) néces-
saires  pour faire apparaître  les premiers signes  d'ano-
malies  fonctionnelles ou morphologiques chez  les animaux
de laboratoire.

1.2  Effets sur la santé découlant d'une réduction de l'ozone
stratosphérique sous l'action des chlorofluorocarbures

    Au  cours  de  la dernière  décennie,  une  inquiétude
croissante  s'est manifestée quant aux  conséquences d'une
réduction de la couche d'ozone dans la  haute  atmosphère,
qui entraînerait du même coup un accroissement du rayonne-
ment UV-B à la surface du globe.  Selon le scénario adopté
pour les émissions de chlorofluorocarbures et d'autres gaz
en  traces, les modèles utilisés permettent de prévoir que
d'ici une cinquantaine d'années, la réduction de la couche
d'ozone sera de 1 à 10%.

    Parmi  les effets possibles sur la santé humaine, on a
très  largement étudié l'induction de  cancers cutanés non
mélanomateux,  tant du point  de vue épidémiologique  chez
l'homme  qu'au  laboratoire  sur l'animal.   On  admet  en
général  que  l'incidence  des  cancers  non  mélanomateux
augmentera par suite de la réduction de la couche d'ozone.
Selon une estimation fondée sur des données  récentes,  on
prévoit  qu'une réduction de  l'ozone atmosphérique de  1%
conduirait  à une augmentation  de 3% de  l'incidence  des
cancers  cutanés non mélanomateux.  Une réduction de 5% de
la  couche d'ozone augmenterait l'incidence de ces cancers
de  16%.   Cette  dernière valeur  signifie  qu'au  niveau
mondial, on enregistrerait plus de 200 000 nouveaux cas de
cancer  de ce type  chaque année, principalement  chez les
individus à peau claire.

    On  a de  plus en  plus de  raisons de  penser que  le
rayonnement  UV-B joue également un  rôle dans l'induction
et  le  développement  des  mélanomes,  un  cancer  cutané
beaucoup  plus  grave.   Toutefois  les  incertitudes  qui
subsistent  quant  à  la relation  dose-effet rendent très
difficiles  les prévisions quantitatives.  Il faut en tout
cas prendre en compte la possibilité d'une augmentation de
la fréquence des mélanomes.

    Chez   l'animal  d'expérience,  le   rayonnement  UV-B
produit  divers  types  d'immunosuppression.  Celle-ci  se
traduit:  (a)  par  une  moindre  résistance  aux  tumeurs
implantées  induites par  les UV-B  et par  un plus  grand
développement de ces tumeurs chez les souris; (b)  par  la
suppression  de la sensibilisation  par les allergènes  de

contact  et (c)  par la  suppression de  la  réaction  aux
allergènes  chez  les  animaux sensibilisés.   On constate
également  une  perturbation  de  la  réponse  immunitaire
contre  certains agents infectieux,  qu'on a pu  mettre en
évidence  dans  le cas  d' Herpes  simplex et de  Leishmania
sp.    On peut en déduire qu'une immunosuppression du même
type pourrait se produire chez l'homme par  suite  d'expo-
sition au rayonnement UV-B.  Les cellules langerhansiennes
cutanées  qui présentent l'antigène sont endommagées et il
s'ensuit  une  dépression des  réponses allergiques.  Bien
qu'on  ait encore beaucoup à apprendre sur ces phénomènes,
il ne faut pas négliger la possibilité d'effets immunosup-
presseurs  et, par voie  de conséquence, une  augmentation
dans  l'incidence  de certaines  maladies infectieuses par
suite d'une diminution de l'ozone stratosphérique.

    On  a des raisons  de penser que  le rayonnement  UV-B
favorise  la formation de cataractes, une cause importante
de  cécité, en particulier  dans les régions  peu  médica-

2.  Effets sur l'environnement

    A  part la théorie selon laquelle les chlorofluorocar-
bures  contribuent  à  l'effet  de  serre,  on  ne dispose
d'aucune  preuve  d'effets écologiques  directs imputables
aux  chlorofluorocarbures examinés dans la  présente mono-
graphie.   Les études relatives aux  effets du rayonnement
UV-B  sur les végétaux sont essentiellement consacrées aux
plantes  cultivées et ont généralement été menées sous des
latitudes  tempérées.  Ces régions ne  représentent qu'une
faible  part des grands  écosystèmes de la  planète.  Bien
qu'en  raison de la complexité  des études expérimentales,
il  subsiste un grand  nombre d'incertitudes à  cet égard,
les données qui sont d'ores et déjà  disponibles  montrent
que  le  rendement des  récoltes  aurait à  souffrir  d'un
accroissement  du rayonnement UV-B  solaire.  Sur plus  de
200 espèces et variétés dont on a étudié la  tolérance  au
rayonnement  ultra-violet, les deux tiers environ s'y sont
révélés  sensibles.  Parmi les plantes  les plus sensibles
figurent les pois, les haricots, les melons,  la  moutarde
et  le chou.  Les membres de la famille des graminées sont
généralement moins sensibles.

    On  peut  observer expérimentalement  qu'il existe une
certaine  tolérance au rayonnement UV-B dans le patrimoine
génétique. Cette conclusion est tirée du fait qu'il existe
des variations importantes dans la sensibilité au rayonne-
ment  UV parmi les diverses variétés de plantes cultivées.
Les  fondements génétiques de cette  sensibilité restent à

    On  a étudié l'effet d'un accroissement du rayonnement
UV-B  sur la qualité  des récoltes.  En  exposant diverses
variétés de soja à un rayonnement UV qui résulterait d'une

réduction de 25% de la couche d'ozone, on a  constaté  que
la  teneur en protéines  et en huile  des graines de  soja
diminuait dans une proportion pouvant atteindre 10%.

    Les  études relatives aux  effets du rayonnement  UV-B
sur la production forestière restent limitées.  Les résul-
tats obtenus ne concernent que les jeunes plants  et  cor-
respondent  à  des niveaux  d'exposition qui résulteraient
d'une  réduction de 40% de la couche d'ozone.  Ces travaux
font état d'une réduction de la croissance et de la photo-
synthèse après exposition de plants de  Pinus taeda.  L'ex-
périence  montre  qu'un accroissement  du rayonnement UV-B
peut  provoquer  une  modification dans  la  structure des
populations arborales.

    On a montré que le rayonnement UV-B  pouvait  affecter
les  constituants  végétaux  et  animaux  des  écosystèmes
marins.   Ces effets se traduisent par une réduction de la
fécondité,  de  la croissance,  de  la survie  et d'autres

3.  Conclusions

    Les  données  toxicologiques sur  les chlorofluorocar-
bures  complètement  halogénés examinées  dans la présente
monographie  montrent que ces produits n'ont qu'une faible
toxicité  aiguë  et  chronique et  qu'ils  sont  dépourvus
d'activité  mutagène ou cancérogène.  Les  risques pour la
santé  humaine sont limités aux cas d'exposition occasion-
nelle  à  de  fortes  concentrations  susceptibles  de  se
produire  lors  de la  manipulation  de ces  produits.  En
revanche, les effets indirects résultant de l'accumulation
de   ces   substances  dans   la  stratosphère  pourraient
entraîner des effets non négligeables sur la santé humaine
dus  principalement à l'accroissement du  rayonnement UV-B
résultant  de la réduction  de la couche  d'ozone stratos-
phérique.   L'accroissement prévisible de  l'incidence des
cancers  cutanés  non  mélanomateux, la  possibilité d'une
augmentation des mélanomes ainsi que les effets immunosup-
presseurs  et ophtalmologiques, sont autant d'éléments qui
incitent  à  conclure  à la  nécessité  d'une  coopération
internationale  immédiate et efficace  pour éviter que  la
couche d'ozone ne se réduise davantage.


1.  La  base de données toxicologiques relative à certains
    chlorofluorocarbures, en particulier ceux qui contien-
    nent  de l'hydrogène, est insuffisante  pour permettre
    une  évaluation  quantitative du  risque.  Il faudrait
    obtenir  davantage  de renseignements  sur la toxicité
    chronique,  la cancérogénicité, les effets tératogènes
    et les effets sur la fonction de reproduction  de  ces
    composés,  en particulier par suite  d'expositions par

2.  On  trouvera résumée au Tableau 16  une évaluation des
    effets  exercés  par  l'accroissement  du  rayonnement

Tableau 16.  Effets potentiels d'un accroissement du rayonnement UV-B
résultant d'une diminution de la couche d'ozone stratosphériquea
Effets                       Niveau des       Impact planétaire 
                             connaissances    potentiel
Cancers cutanés              Moyen à élevé    Moyen
Système immunitaire          Faible           Elevé
Cataracte                    Moyen            Faibleb
Florec                       Faible           Important
Faune et flore aquatiquesc   Faible           Important
Impact climatologiqued       Moyen            Moyen
Ozone ambian                 Moyen            Faiblee
a  Tiré, avec des modifications, de SAB-EC-87-025  Review of EPA's 
   Assessment of the Risks of  Stratospheric Modification par le 
   Stratospheric Ozone Subcommittee, Science Advisory Board, US 
   Environmental Protection Agency, Mars 1987. 
b  Une réflexion récente à propos de l'influence de la réduction 
   de la couche d'ozone sur l'incidence de la cataracte conduit à 
   considérer que l'impact pourrait en être plus grave (US EPA, 
   Assessing the Risks of Trace Gases that can modify the 
   Stratosphere, Chapitre 10, Decembre 1987). 
c  Voir section 6.
d  Influence de la réduction de l'ozone stratosphérique elle-même 
   et des gaz qui sont à l'origine de cette réduction sur le 
   climat, y compris l'élévation du niveau des mers. 
e  L'impact pourrait être important dans certains secteurs urbains 
   ou ruraux caractérisés par des problèmes de pollution par 
   l'ozone au niveau du sol, à l'échelon régional ou local. 

    Il faut poursuivre les recherches dans les secteurs où
les  connaissances  restent  insuffisantes et  où l'impact
potentiel  au niveau planétaire est  important.  Il s'agit
de  huit secteurs où  une évaluation sera  nécessaire dans
l'avenir  et qui sont particulièrement  importants pour la
compréhension  des effets dus  à la réduction  de  l'ozone
atmosphérique et la conduite à tenir devant  ces  phénomè-
nes; il faut donc:

*   étudier  les mécanismes de l'immunosuppression sur des
    modèles animaux et chez l'homme;

*   déterminer quelles maladies infectieuses comportent un
    stade ou un processus susceptibles d'être aggravés par
    une  exposition au rayonnement UV-B et mettre au point
    des modèles pour expliquer ces pathologies;

*   étudier  les  effets  d'une exposition  au rayonnement
    UV-B  sur l'incidence des maladies  infectieuses et en
    particulier  examiner dans quelle mesure  elles dépen-
    dent  de la longueur  d'onde et établir  des relations
    dose-réponse chez l'homme;

*   déterminer  l'impact  de  l'immunosuppression  par  le
    rayonnement UV-B sur l'efficacité des vaccins;

*   clarifier  le  rôle  des modifications  immunologiques
    dans l'apparition des mélanomes et des cancers cutanés
    non  mélanomateux sous l'action du  rayonnement ultra-

*   déterminer  le spectre d'action et les relations dose-
    effet dans le cas de l'induction de  différents  types
    de mélanomes par le rayonnement ultra-violet;

*   mettre  au point une meilleure définition des spectres
    d'action relatifs à l'induction des épithélomas spino-
    cellulaires et en particulier des épithéliomas cutanés
    baso-cellulaires par rayonnement ultra-violet;

*   étudier la biologie et l'épidémiologie de la cataracte
    et  développer des méthodes  permettant de réduire  le
    risque d'affections oculaires.

3.  Certaines  autorités recommandent encore l'utilisation
    du  CFC-11 et du CFC-12 comme gaz propulseurs dans les
    bombes  aérosol utilisées pour la désinsectisation des
    aéronefs.   Il y a nécessité urgente à mettre au point
    un  gaz  propulseur d'un  type nouveau, ininflammable,
    sûr,  non irritant et qui se s'attaque pas à la couche
    d'ozone car les anciens produits sont d'ores  et  déjà
    interdits dans de nombreux pays.

4.  Une coopération internationale efficace est nécessaire
    pour  éviter que la couche  d'ozone stratosphérique ne
    se  réduise davantage et  pour cela, il  faut  réduire
    d'au  moins 80 à 90% les émissions de chlorofluorocar-
    bures qui détruisent l'ozone.  Il faut en premier lieu
    trouver des substituts à ces produits, après quoi l'on
    devra  imaginer des méthodes qui permettent d'éliminer
    dans de bonnes conditions les déchets de chlorofluoro-
    carbures existants.  Il est recommandé à tous les pays
    de prendre des dispositions pour réduire l'utilisation
    de  chlorofluorocarbures  ayant  une forte  tendance à
    détruire l'ozone stratosphérique.


1.  Identidad, propiedades físicas y químicas, y métodos analíticos

    La  presente monografía trata sólo de los clorofluoro-
carbonos (CFC) derivados de la sustitución completa de los
átomos  de hidrógeno del metano  y el etano por  átomos de
flúor y cloro. Muchos de esos productos tienen importancia
comercial  y se sabe que algunos de ellos contribuyen a la
disminución  del  ozono.   Los productos  examinados en el
presente  informe son los siguientes: triclorofluorometano
(CFC-11),  diclorodifluorometano   (CFC-12),  clorotrifluoro-
metano  (CFC-13), 1,2-difluoro-1,1,2,2-tetracloroetano (CFC-
112),  1,1-difluoro-1,2,2,2-tetracloroetano  (CFC-112a), 1,1,2-
tricloro-1,2,2-trifluoroetano  (CFC-113),  1,1,1-tricloro-2,2,2-
trifluoroetano   (CFC-113a),   1,2-dicloro-1,1,2,2-tetrafluoro-
etano (CFC-114), 1,1-dicloro-1,2,2,2-tetrafluoroetano  (CFC-
114a) y 1-cloro-1,1,2,2,2-pentafluoroetano (CFC-115).  No se
examinan  los productos que  no contienen cloro  (como  el
CFC-134a  y  el  CFC-116).  Los  productos  que  contienen
hidrógeno (como el clorodifluorometano) se considerarán en
un informe ulterior.

    Los  clorofluorocarbonos comerciales figuran entre los
productos  químicos orgánicos de mayor pureza disponibles.
Se caracterizan habitualmente por una presión de  vapor  y
una densidad elevadas y por valores bajos  de  viscosidad,
tensión superficial, índice de refracción y solubilidad en
agua.  El grado de  sustitución por flúor  influye grande-
mente en las propiedades físicas y, en general,  a  medida
que  aumenta la sustitución por flúor, se eleva la presión
de  vapor y disminuyen el punto de ebullición, la densidad
y la solubilidad en agua.

    Los  clorofluorocarbonos  examinados  en  la  presente
monografía  son razonablemente estables desde  el punto de
vista  químico y, en ausencia  de catalizadores metálicos,
presentan  bajas tasas de hidrólisis.  Son muy resistentes
al ataque por los agentes oxidantes convencionales en tem-
peraturas  inferiores a 200 °C. Por lo general, los cloro-
fluorocarbonos  presentan un elevado grado  de estabilidad
térmica  y son extremadamente resistentes a casi todos los
reactivos químicos.  Sin embargo, reaccionan violentamente
con los metales dotados de reactividad química.

    Se dispone de varios métodos analíticos para la deter-
minación  de los clorofluorocarbonos en  distintos medios.
Comprenden  la  espectrofotometría,  la  cromatografía  de
gases  con varios métodos de cuantificación y la espectro-
metría  de masa.  La mayor parte de los métodos emplean la
cromatografía  de gases con  distintas técnicas de  detec-
ción; los límites de detección suelen ser del orden de una
parte  por billón (ppb).  Se han modificado los métodos de
recogida  de muestras para aumentar su selectividad y sen-

2.  Fuentes de exposición humana y ambiental

    Conforme  a los conocimientos actuales,  los cloroflu-
orocarbonos   examinados  en  la  presente  monografía  no
aparecen  naturalmente  en  el medio  ambiente,  pero casi
todos los clorofluorocarbonos, excepto los utilizados como
productos  intermedios químicos, pasan al  medio ambiente.
La  producción mundial estimada de los clorofluorocarbonos
con  posibilidades  importantes  de  reducción  del  ozono
(CFC-11, CFC-12, CFC-113) en 1985 fue por lo menos  de  un
millón  de toneladas.  La fabricación no se halla limitada
a  los principales países industriales y se realiza por lo
menos en 16 países.  Al aplicarse el Protocolo de Montreal
probablemente  se invertirá la actual tendencia al aumento
en la fabricación de esos clorofluorocarbonos.

    El método más importante de fabricación de los princi-
pales  clorofluorocarbonos es el desplazamiento catalítico
del cloro presente en los clorocarbonos por flúor mediante
la reacción con fluoruro de hidrógeno anhidro.   La  mayor
parte  de  la  liberación  al  medio  ambiente  se produce
durante  la eliminación del equipo de desecho que contiene
refrigerante  y  no  en el  curso  de  la fabricación,  el
almacenamiento ni la manipulación. La emisión de cloroflu-
orocarbonos  propulsantes ha disminuido como  resultado de
las  restricciones  legislativas  impuestas a  su  uso  en
numerosos países, y la liberación de agentes de relleno es
escasa. Dada la elevada presión de vapor de esos productos
en  las  temperaturas  ambientales, casi  toda la cantidad
liberada  al medio ambiente se acumula en definitiva en la
atmósfera.  La emisión anual estimada en alrededor  de  un
millón  de toneladas en  1985 consistió principalmente  en
CFC-11  y  CFC-12, y  la  liberación acumulativa  de  esos
clorofluorocarbonos de 1931 a 1985 fue de 13,5 millones de
toneladas aproximadamente.

    La  distribución mundial aproximada del  uso de cloro-
fluorocarbonos  en 1985  fue la  siguiente: refrigerantes,
15%;  agentes  de  relleno de  espuma, 35%;  impulsores de
aerosoles, 31%; varios, 7%, y sin designar, 12%.   En  los
Estados  Unidos  de América,  el  empleo de  impulsores de
aerosoles  fue  muy  inferior debido  a  las restricciones

3.  Transporte, distribución y transformación en el medio ambiente

    Los  clorofluorocarbonos  comerciales persisten  en el
medio  ambiente  debido  a su  estabilidad  química.   Los
tiempos medios de presencia en la atmósfera se calculan en
65,  110,  400,  90, 180  y  380 años  para el  CFC-11, el
CFC-12,  el CFC-13, el CFC-113,  el CFC-114 y el  CFC-115,
respectivamente.   Esos prolongados periodos  de presencia
aseguran  la  difusión a  la  estratosfera, en  donde  los
clorofluorocarbonos  reaccionarán con la capa de ozono por
medio  de los átomos de  cloro liberados por un  mecanismo

fotoquímico.  Además esos productos contribuirán al efecto
de invernadero.

4.  Niveles ambientales y exposición humana

    Varios  investigadores han señalado que  los cloroflu-
orocarbonos  presentan  una distribución  mundial.  Se han
medido  recientemente las variaciones latitudinales de las
concentraciones  de  clorofluorocarbonos y  se han hallado
escasas  diferencias  en  las concentraciones  de CFC-11 y
CFC-12  entre los hemisferios septentrional  y meridional.
Tampoco hay una variación notable en relación con la alti-
tud hasta 6 km por encima de la superficie de  la  tierra.
Las  concentraciones medidas de clorofluorocarbonos  en el
aire  de las zonas urbanas-suburbanas son superiores a las
registradas  en las zonas rurales-remotas debido a la con-
tribución de las fuentes locales de emisión.

    Las  concentraciones  atmosféricas de  CFC-11 y CFC-12
aumentaron  constantemente hasta 1985,  año en el  que los
niveles  combinados de esos  dos productos en  los Estados
Unidos  de  América  eran  de  9120 ng/m3    en  las zonas
urbanas-suburbanas, y de 2720 ng/m3 en  las zonas rurales-
remotas para ambas sustancias.  Partiendo de esos datos se
ha  calculado que  la inhalación  humana es  de 182  y  54
mg/día en esos dos tipos de zonas.

    Las  concentraciones medias en la  superficie oceánica
de  CFC-11  y  CFC-12, registradas  en tres emplazamientos
distantes entre sí, eran del orden de  O,2 ng/litro.   Sin
embargo,  se  midieron valores  de  0,62 ng de  CFC-11 por
litro  en  el  mar  de  Groenlandia  en  1982 y  hasta  de
0,54 ng/litro  en las aguas  costeras del Japón.   En esas
mismas  aguas  se  registró  el  valor  máximo  de CFC-12:
0,33 ng/litro.  Se han medido niveles mucho más  altos  en
las  aguas dulces del lago  Ontario: 249 mg de CFC-11  por
litro y 572 ng de CFC-12 por litro.  No se  han  detectado
los clorofluorocarbonos en el agua de beber, pero  se  han
hallado en la nieve y el agua de lluvia en Alaska, el lago
Ontario y el río Niágara.  Se ha detectado la presencia de
CFC-11  en concentraciones de 0,1-5 µg/kg   (ppb) (peso en
seco)  en distintos órganos  de pescados y  moluscos.  Sin
embargo,  no se ha probado la presencia de clorofluorocar-
bonos en los alimentos tratados.

5.  Cinética y metabolismo

    Los  clorofluorocarbonos pueden penetrar en  el organ-
ismo  humano por inhalación, ingestión o contacto cutáneo.
La inhalación es la vía de entrada más corriente e import-
ante, mientras que la espiración es la forma  de  elimina-
ción  del organismo más significativa.   Los estudios con-
trolados con voluntarios y animales de experimentación han
proporcionado  datos interesantes respecto a la exposición
a  distintos clorofluorocarbonos.  Esos datos  indican que
los clorofluorocarbonos:

*   pueden  absorberse por la membrana alveolar, el tracto
    gastrointestinal o la piel;

*   pasan con rapidez a la sangre, después de  la  inhala-

*   pasan a la sangre a una tasa decreciente  al  aumentar
    la concentración sanguínea;

*   una  vez presentes en  la sangre, son  absorbidos  por
    distintos tejidos;

*   alcanzan  una  concentración  sanguínea estable  si la
    exposición  es  suficientemente  larga,  indicando  la
    existencia de un equilibrio entre el aire que contiene
    clorofluorocarbonos y la sangre;

*   se  absorben todavía por los tejidos orgánicos después
    de  la  estabilización  inicial  de  la  concentración
    sanguínea, y siguen penetrando en el organismo.

    Los  estudios efectuados en animales  muestran que los
clorofluorocarbonos  se absorben con rapidez después de la
inhalación  y se distribuyen a través de la sangre en casi
todos  los tejidos del organismo.   Las mayores concentra-
ciones se encuentran habitualmente en los tejidos adiposos
o  que contienen lípidos. Sin embargo, los clorofluorocar-
bonos  se hallan también  en órganos bien  irrigados,  por
ejemplo,  el  corazón,  los  pulmones,  los  riñones  y la

    Los  resultados de estudios metabólicos  efectuados en
el  hombre y los animales han demostrado la resistencia de
los clorofluorocarbonos a descomponerse o experimentar una
transformación metabólica en los sistemas biológicos. Esos
resultados  permiten pensar que los clorofluorocarbonos se
metabolizan  en general en  cuantía escasa o  incluso nula
después de la exposición.

    Cualquiera que sea la vía de entrada, los clorofluoro-
carbonos  se  eliminan  casi exclusivamente  por  las vías
respiratorias  en el aire espirado.  No se ha señalado una
recuperación significativa de clorofluorocarbonos o de sus
metabolitos en los estudios que han tratado de identificar
productos  de  transformación metabólica  eliminados en la
orina o las heces.

6  Efectos en el medio ambiente

    Ciertos clorofluorocarbonos, en particular los CFC-11,
12,  113, 114 y 115,  son extremadamente estables  en  las
condiciones  reinantes en la atmósfera baja.  Los procesos
fotolíticos  que separan el  cloro de los  clorofluorocar-
bonos no se producen hasta que esos gases emigran al medio
de  radiación de alta energía de la estratosfera superior.

Entonces  los  radicales  cloro  destruyen  el  ozono  por
catálisis.   El ozono estratosférico absorbe  la radiación
ultravioleta  solar  (UV-  B: 280-320 nm  de  longitud  de
onda), permitiendo que penetre hasta la superficie  de  la
tierra sólo una cantidad reducida de radiación UV-B.

    Los  datos experimentales indican que un aumento de la
irradiación UV-B en la superficie terrestre, resultante de
la disminución del ozono, ejercería efectos nocivos en los
biotas  terrestres y acuáticos.  Pese a las incertidumbres
resultantes  del  carácter  complejo de  los  experimentos
prácticos,  los  datos  actualmente  disponibles  permiten
pensar que el rendimiento de las cosechas y  la  producti-
vidad  de los  bosques son  vulnerables al  aumento de  la
radiación  de  UV-B  solar.  Los  datos existentes indican
también  que el incremento de la radiación UV-B modificará
la  distribución y abundancia de las plantas y cambiará la
estructura del ecosistema.

    Varios   estudios  de  los  ecosistemas   marinos  han
demostrado  que  la radiación  UV-B  produce daños  en las
larvas de los peces y los peces de poca edad,  las  larvas
de  camarones  y cangrejos,  los  copépodos y  las plantas
indispensables  para la red alimentaria marina.  Entre los
efectos dañinos figuran el descenso de la  fecundidad,  el
crecimiento  y la supervivencia.  Los datos experimentales
indican que incluso pequeños aumentos de la  exposición  a
la  radiación UV-B ambiental  pueden dar lugar  a  cambios
notables del ecosistema.

7.  Efectos en animales de experimentación y sistemas  in vitro

    Se  ha  estudiado  ampliamente la  toxicidad aguda por
inhalación de clorofluorocarbonos. Los clorofluorocarbonos
examinados  en la presente monografía presentan una escasa
toxicidad  aguda por inhalación.  La  sintomatología de la
intoxicación   aguda  comprende  efectos  en   el  sistema
nervioso  central (SNC), efectos secundarios en el sistema
cardiovascular  e  irritación  de las  vías respiratorias.
Los  limitados datos disponibles  sobre la toxicidad  oral
aguda  de  los  clorofluorocarbonos muestran  que es baja.
Cuando se aplican en la piel en dosis altas,  el  CFC-112,
el  CFC-112a  y el  CFC-113  provocan distintos  grados de
irritación, pero ningún otro efecto notable.

    Se   han  comunicado  estudios de  inhalación  a corto
plazo  del CFC-11, el CFC-12,  el CFC-112, el CFC-113,  el
CFC-114  y el CFC-115.   Los resultados muestran  una baja
toxicidad   y  los  efectos  observados  guardan  relación
principalmente  con el SNC,  las vías respiratorias  y  el
hígado.   Los estudios de toxicidad oral han confirmado la
reducida toxicidad.

    En  un estudio de inhalación a largo plazo se expuso a
ratas  al CFC-113 al 0,2, 1 ó 2% (15,3, 76,6, ó   183 g/m3),

6 horas por día, 5 días por semana, hasta 2 años.   No  se
observaron  efectos histopatológicos ni  modificaciones de
los  valores de laboratorio clínico.  La única observación
que  los  autores  consideraron relacionada  con el trata-
miento  fue la disminución del aumento de peso corporal en
los grupos expuestos a las dos dosis más altas.

    Los datos disponibles muestran que los clorofluorocar-
bonos  totalmente  halogenados  evaluados en  la  presente
monografía  tienen  escaso  o nulo  potencial  mutágeno  o
carcinógeno. Se han obtenido resultados negativos in vitro
utilizando   bacterias y células  de mamífero, con  o  sin
activación metabólica, en la prueba letal dominante.

    Los  estudios de cancerogenicidad  a largo plazo  (por
vía oral y por inhalación) con CFC-11 y CFC-12, efectuados
en  ratas  y  ratones, dieron  resultados  negativos.   Se
observó  una respuesta tumorígena  en la cavidad  nasal en
ratas  sometidas  a la  inhalación  de CFC-113,  pero  esa
reacción  se consideró equívoca.  Los  tumores presentaron
distintas  morfologías  y  las  incidencias  no  guardaban
relación con la dosis. Aunque se utilizan los clorofluoro-
carbonos  desde hace más de 50 años, sólo se dispone de un
estudio  de  cohorte (539 trabajadores  expuestos).  No se
observó  ningún aumento de la  mortalidad total ni de  las
defunciones por tumores.

    Entre  los  ocho clorofluorocarbonos  examinados en el
presente  documento,  en  las  publicaciones   científicas
disponibles se han recogido estudios sobre efectos tóxicos
en el desarrollo en los casos del CFC-11, el CFC-12  y  el
CFC-113.   En ninguno de esos  tres clorofluorocarbonos se
han  registrado indicios de embriotoxicidad, fetotoxicidad
o teratogenicidad.

8.  Efectos en la especie humana

    Los estudios controlados de voluntarios que utilizaron
CFC-11  y CFC-12 no  mostraron efectos observables  en los
parámetros  hematológicos y químicos clínicos,  el ECG, el
EEG, la función pulmonar o la exploración neurológica.

    En  concentraciones altas, los  sujetos experimentaron
una sensación de picazón, zumbidos de oídos  y  aprensión.
Se  observaron modificaciones del EEG,  alocución difícil-
mente  inteligible y disminución  de la habilidad  en  las
pruebas  psicológicas.  La exposición a  una concentración
del  11%a   (545 g/m3)   de CFC-12 durante 11 minutos pro-
vocó  un grado importante de arritmia cardiaca, seguido de
un  descenso de la  conciencia con amnesia  al cabo de  10
a   En la totalidad de la presente monografía, los porcentajes 
    de clorofluorocarbonos en el aire se expresan como el volumen de 
    clorofluorocarbono dividido por el volumen de aire.

    Tras la exposición al CFC-12 a una  concentración  del
1%  (50 g/m3)   durante 150 minutos se observó un descenso
del  7%  en los  índices  de pruebas  psicomotrices,  pero
ningún  efecto con una concentración  del 0,1%   (5 g/m3).

    En   un  estudio  en  el  que  10  sujetos  estuvieron
expuestos al CFC-11, el CFC-12 y el CFC-114,  dos  mezclas
de  CFC-11 y  CFC-12, y  una mezcla  de CFC-12  y  CFC-114
(concentraciones  en el aire respirado  comprendidas entre
16 y 150 g/m3)   durante 15, 45 ó 60 segundos, se registró
en  cada caso una reducción  aguda importante de la  capa-
cidad  pulmonar  ventilatoria  (FEF50,  FEF25),  así  como
bradicardia, aumento de la variabilidad del ritmo cardiaco
y bloqueo auriculoventricular.

    Se  evaluó  la  habilidad  psicomotriz  utilizando  el
CFC-113  en  concentraciones  de 0,15%  (12 g/m3),   0,25%
(19 g/m3),   0,35% (27 g/m3)   ó 0,45% (35 g/m3)   durante
165 minutos.  La concentración más baja careció de efecto,
pero  se  produjeron  dificultades para  la  concentración
mental  y cierto descenso en los resultados de las pruebas
a partir de la dosis de 0,35% (27 g/m3).

    Los  limitados estudios efectuados muestran que en las
personas  con antecedentes de reacción cutánea a los deso-
dorantes  en pulverización que contienen  CFC-11 o CFC-12,
la aplicación cutánea de ciertos clorofluorocarbonos puede
provocar  una sensibilización. En cinco  personas no fuma-
doras,  la función mucociliar traqueal no se alteró por la
exposición al CFC-11.

    Dos  estudios permiten pensar  que la exposición  pro-
fesional normal al CFC-113 no plantea un riesgo grave para
la  salud.  No se  observaron efectos adversos  en niveles
profesionales  de  hasta  el 0,47%  (36,7 g/m3),   con una
concentración media del 0,07% (5,4 g/m3).

    En  varios  estudios  se ha  observado una disminución
aguda  importante de la capacidad pulmonar ventilatoria en
los  peluqueros que utilizan pulverizaciones  para el pelo
que  contienen  clorofluorocarbonos.   Se  han  registrado
casos  de efectos neurológicos atribuidos  a la exposición
profesional  a los clorofluorocarbonos.  Se ha descrito un
caso de neuropatía en un trabajador de lavandería expuesto
al  tetracloroeteno y a concentraciones  indeterminadas de
CFC-113 durante seis años.

    Se  ha notificado también la exposición no profesional
y  accidental o la  inhalación por uso  indebido de  aero-
soles,  siendo los principales  síntomas la depresión  del
SNC  y las reacciones cardiovasculares.   La arritmia car-
diaca,  agravada  posiblemente  por los  niveles  altos de
catecolaminas  provocados por el  estrés o por  la  hiper-
capnia  moderada, se considera la causa de esas respuestas
adversas, que pueden conducir a la muerte.

    Es de suponer que la mayor radiación de UV-B conducirá
a  efectos predominantemente adversos en  la salud humana,
pero  el estado de  conocimientos varía grandemente  de un
efecto a otro. Casi todos los autores admiten  que  aumen-
tará  la incidencia de los cánceres cutáneos distintos del
melanoma.   Las  previsiones  basadas en  datos  recientes
muestran que esa incidencia se incrementará en un  3%  por
cada  1% de pérdida de ozono.  Sobre esa base, una pérdida
de  ozono del 5% conduciría, al cabo de varios decenios, a
la  aparición cada año de más de 200 000 casos adicionales
de cánceres cutáneos distintos del melanoma.

    La radiación UV-B parece intervenir también en la for-
mación  de los melanomas  cutáneos, tumores de  mayor gra-
vedad.   Sin embargo, los conocimientos  son insuficientes
para   establecer  con  precisión  las  relaciones  dosis-

    El sistema inmunitario experimenta la influencia de la
radiación UV-B de distintos modos.  Aunque no  se  dispone
de  conocimientos  suficientes para  predecir las consecu-
encias de la disminución de ozono en la salud  humana,  se
observará  probablemente  una  mayor incidencia  de enfer-
medades infecciosas.

    El  efecto más importante para  el ojo humano será  un
aumento  de la incidencia  de la catarata,  enturbiamiento
permanente del cristalino del ojo que conduce, incluso con
los actuales niveles de radiación UV-B, a alteración de la
visión y ceguera en muchas personas.
    Puede  esperarse que el  aumento de la  radiación UV-B
incremente  el "smog" fotoquímico, lo  que agravaría los
problemas de salud conexos en las zonas urbanas  e  indus-

9.  Evaluación de los riesgos para la salud humana

    Los efectos directos más importantes que provoca en el
ser  humano  la  exposición a  los  clorofluorocarbonos se
deben  a  las  concentraciones  excesivas  resultantes  de
accidentes industriales y del uso indebido o  excesivo  de
esas  sustancias como disolventes o  gases impulsores.  La
liberación  de  clorofluorocarbonos  en el  medio ambiente
mundial  en el curso de  la eliminación de desechos  y del
transporte   y  almacenamiento  son  motivo  de  creciente
preocupación,  debido  a  los posibles  efectos  que  esas
liberaciones  incontroladas  pueden  ejercer en  la  salud
futura de la humanidad.


1.  Evaluación de los riesgos para la salud humana

1.1  Efectos directos en la salud resultantes de la exposición
a clorofluorocarbonos totalmente halogenados

    La  cinética y el  metabolismo de los  clorofluorocar-
bonos se caracterizan por la absorción y  la  distribución
pulmonares rápidas. No hay indicio de ninguna acumulación.
La  transformación  metabólica de  los clorofluorocarbonos
examinados  en la presente monografía  es despreciable, si
es  que realmente existe.   Por consiguiente, los  efectos
tóxicos  de los metabolitos  son muy improbables.  La tox-
icidad  aguda de los clorofluorocarbonos es muy baja, como
se  demuestra en estudios efectuados en distintas especies
animales  con diferentes vías de administración. Se carac-
teriza  por los efectos en  el corazón, el sistema  respi-
ratorio  y a veces el hígado.  Esos efectos concuerdan con
la  sintomatología  observada en  intoxicaciones agudas en

    Tras la exposición repetida pueden observarse síntomas
clínicos  comparables.   Se producen  a veces alteraciones
hepáticas y renales.  En el hombre aparecen síntomas en el
SNC,  el sistema cardiovascular y  el aparato respiratorio
en  los casos de uso indebido intenso y de exposición pro-
fesional incontrolada o accidental.  En las condiciones de
uso  que suponen la exposición a corto plazo a una concen-
tración  de  hasta 1000 ppm,  no  son de  esperar  afectos
adversos en la salud.

    La  evaluación de los estudios  efectuados en animales
de  experimentación no muestra que haya riesgo de cancero-
génesis  para el ser humano.   Lo subraya el hecho  de que
los  clorofluorocarbonos  examinados en  la presente mono-
grafía  están  desprovistos de  genotoxicidad en distintos
puntos  finales mutagénicos y  transformaciones celulares.
En  un  estudio de  cohorte  limitado que  comprendió  539
trabajadores  expuestos, no se registró aumento de la mor-
talidad ni de la frecuencia de tumores. Los estudios sobre
la  influencia en la reproducción  (fecundidad, embriotox-
icidad,  fetotoxicidad,  teratología) y  sobre los efectos
generales  en el desarrollo en animales de experimentación
han  sido constantemente negativos.  No  se han registrado
efectos  en la reproducción humana, incluido el desarrollo
intrauterino y posnatal.

    Se han medido concentraciones medias en el aire de las
zonas  urbanas-suburbanas de 3,4 µg/m3     de  CFC-11 y de
6 µg/m3      de CFC-12.  En las zonas rurales-remotas, los
niveles  correspondientes fueron de 1,0 µg/m3      para el
CFC-11 y de 1,6 µg/m3 para el CFC-12.

    Esos niveles de exposición se consideran despreciables
en  comparación  con  las  concentraciones  de  25 000   a
50 000 µg/m3      (~5000   a 10 000 ppm) que causan signos
iniciales  de  alteraciones funcionales  o morfológicas en
los animales de laboratorio.

1.2  Efectos en la salud previstos provocados por la reducción del
ozono estratosférico causada por los clorofluorocarbonos

    En  el último decenio  se ha producido  una  creciente
preocupación  por las consecuencias de  la disminución del
ozono en la atmósfera superior, con el  aumento  consigui-
ente de la radiación UV-B en la superficie de  la  tierra.
Los  cálculos en modelos predicen, para los próximos cinco
años,  una pérdida de ozono  comprendida entre el 1%  y el
10%,  en función del supuesto utilizado para la liberación
de los clorofluorocarbonos y de otros gases  en  oligocon-

    Entre los efectos en la salud humana se ha investigado
ampliamente la inducción de cánceres cutáneos distintos al
melanoma,  tanto en epidemiología humana  como en animales
de  experimentación.  En general  se  ha aceptado  la con-
clusión  de que la  incidencia de esos  cánceres aumentará
como resultado de la disminución del ozono. Una estimación
basada  en  datos recientes  prevé  que una  reducción del
ozono  atmosférico del 1%  conduciría a un  aumento de  la
incidencia de cánceres cutáneos distintos del melanoma del
3%.  Una reducción del ozono  del 5% llevaría a  un incre-
mento  de la incidencia del 16%.  Este último supondría un
aumento mundial de más de 200 000 casos nuevos de cánceres
cutáneos  distintos al melanoma por año, sobre todo en las
personas de piel clara.

    Aumentan los indicios que permiten pensar que la radi-
ación  UV-B interviene también en la inducción y prolifer-
ación del melanoma cutáneo, tipo más grave de cáncer de la
piel. Sin embargo, la incertidumbre existente, en particu-
lar  en lo que respecta  a la relación dosis-efecto,  hace
que  las  predicciones  cuantitativas sean  muy difíciles.
Ahora  bien, debe tomarse en  cuenta la posibilidad de  un
aumento del melanoma cutáneo.

    La radiación UV-B produce distintos tipos de supresión
específica  del  sistema  inmunitario en  los  animales de
experimentación.  Se observa una disminución de la resist-
encia  a los tumores implantados inducida por la radiación
UV-B  y  un  mayor crecimiento  de  tales  tumores en  los
ratones;  además  se  suprime la  sensibilización  por los
alergenos  de contacto y la  respuesta a los alergenos  en
los  animales sensibilizados.  También  se altera la  res-
puesta  inmunitaria frente a ciertos  agentes infecciosos,
como  se ha demostrado en  los casos del virus  del herpes
simple y de las leishmanias.  Existen indicios de  que  la
radiación UV-B puede producir en el hombre  una  supresión

análoga  de  la respuesta  inmunitaria.   En la  piel, las
células  de Langerhans de presentación de antígenos quedan
lesionadas  y disminuyen las respuestas alérgicas.  Aunque
todavía  queda mucho por  aprender en ulteriores  investi-
gaciones,  no  deben  ignorarse los  posibles  efectos  de
supresión  inmunitaria  y  el aumento  consiguiente  de la
incidencia de ciertas enfermedades infecciosas que podrían
resultar de la disminución del ozono estratosférico.

    Ciertos  datos muestran que la  radiación UV-B aumenta
la  formación de la catarata, importante causa de ceguera,
en  particular en las zonas que poseen limitados servicios

2.  Efectos en el medio ambiente

    Aparte  de  la  teoría de  que los clorofluorocarbonos
contribuyen al efecto de "invernadero", no se dispone de
datos   que  señalen  otros  efectos  ecológicos  directos
provocados  por  los clorofluorocarbonos  examinados en la
presente monografía.

    Los estudios sobre los efectos de la radiación UV-B en
las  plantas se han concentrado  en los cultivos y  se han
realizado   en  general  en  latitudes  templadas.   Estas
representan  sólo una pequeña  porción de los  principales
ecosistemas  del mundo. Aunque existen  numerosas incerti-
dumbres  resultantes del carácter  complejo de los  exper-
imentos, los datos actualmente disponibles permiten pensar
que  los cultivos son  posiblemente vulnerables a  mayores
niveles de radiación UV-B solar. Entre más de 200 especies
y  cultivares  examinados respecto  a  la tolerancia  a la
radiación  ultravioleta,  alrededor  del  65%   resultaron
sensibles.   Entre  los  grupos de  plantas  más sensibles
figuraban  los  cultivos  de guisantes,  judías,  melones,
mostaza y coles. Los miembros del sistema de la hierba son
en general menos sensibles.

    Los  datos  experimentales muestran  que el patrimonio
genético  presenta cierto grado  de tolerancia a  la radi-
ación  UV-B.  Se basan en el alto grado de variación en la
sensibilidad  a la radiación  UV observada en  los  culti-
vares.  Todavía tiene que determinarse la base genética de
la sensibilidad.

    Se  ha estudiado el efecto  de los mayores niveles  de
radiación UV-B sobre la calidad de las cosechas.  El  con-
tenido  en proteínas y aceite  de cultivares seleccionados
de  semilla de soja se  redujo hasta en el  10% al exponer
las  plantas a niveles de  radiación UV que simulaban  una
pérdida de ozono del 25%.

    Se  han realizado limitados estudios sobre los efectos
de la radiación UV-B en la productividad  forestal.   Sólo
se  dispone  de resultados  relativos  a los  plantones  y

corresponden  a niveles de  exposición equivalentes a  una
reducción del ozono del 40%.  Esos estudios  muestran  una
disminución  del crecimiento y de  la fotosíntesis después
de  la  exposición  de plantones  de  Pinus  taeda. Ciertos
datos  experimentales  muestran  que  el  aumento  de  los
niveles  de radiación UV-B  puede producir cambios  en  la
estructura del conjunto del bosque.

    Se  ha observado que la exposición a la radiación UV-B
afecta  a los componentes vegetales y animales de los eco-
sistemas marinos.  Entre los efectos figuran los descensos
de la fecundidad, el crecimiento, la supervivencia y otros

3.  Conclusiones

    Los  datos toxicológicos disponibles sobre  los cloro-
fluorocarbonos  totalmente  halogenados  examinados en  la
presente  monografía  muestran  que la  toxicidad  aguda y
crónica es baja y no indican que tengan capacidad mutágena
ni  cancerígena.  Los riesgos  para la salud  humana están
principalmente limitados a exposiciones altas ocasionales,
que  pueden producirse al manipular  esas sustancias.  Por
el  contrario, los efectos  indirectos que aparecen  en el
hombre  por  la  acumulación  de  tales  productos  en  la
estratosfera pueden conducir a alteraciones notables de la
salud humana, producidas sobre todo por la disminución del
ozono  estratosférico, que da  lugar a un  aumento de  los
efectos de la radiación UV-B.  El aumento previsto  en  la
incidencia  de los cánceres  cutáneos distintos del  mela-
noma,  el posible incremento  del melanoma, y  los efectos
inmunotóxicos y oculares conducen a la conclusión  de  que
es  necesaria  una  cooperación internacional  inmediata y
eficaz   para  reducir  toda   nueva  pérdida  del   ozono


1.  La  base de datos sobre la toxicidad de algunos cloro-
    fluorocarbonos,  en  particular  de los  que contienen
    hidrógeno,  es insuficiente para efectuar evaluaciones
    cuantitativas  del  riesgo.   Se necesita  información
    adicional  sobre la toxicidad crónica, la cancerogeni-
    cidad  y  la teratogenicidad/efectos  reproductores de
    los  productos, en particular en  el caso de la  expo-
    sición por inhalación.

2.  En el cuadro 16 se resume la evaluación de los efectos
    del aumento de la radiación UV-B.

Cuadro 16.  Posibles efectos del aumento de la radiación UV-B
resultantes del descenso del ozono estratosféricoa
Efectos               Conocimientos       Posible impacto 
                      disponibles         mundial
Cáncer cutáneo        Moderados a altos   Moderado
Sistema inmunitario   Escasos             Alto
Catarata              Moderados           Bajob
Vida vegetalc         Escasos             Alto
Vida acuáticac        Escasos             Alto
 climáticasd          Moderados           Moderado
Ozono ambiental       Moderados           Bajoe
a   Modificado de SAB-EC-87-025  Review of EPA's Assessment 
     of the Risk of Stratospheric Modification, Stratospheric 
    Ozone Subcommittee, Science Advisory Board, US 
    Environmental Protection Agency, marzo de 1987. 
b   Un estudio más reciente sobre la influencia de la pérdida 
    de ozono en la incidencia de la catarata permite pensar 
    que puede ser más grave (US EPA, Assessing the Risks of 
    Trace Gases that can modify the Stratosphere, Capítulo 
    10, diciembre de 1987). 
c   Véase la sección 6.
d   Contribución a los cambios climáticos, incluido el 
    aumento del nivel del mar, de la propia pérdida del 
    ozono estratosférico y de los gases que causan esa 
e   El impacto puede ser alto en determinadas zonas urbanas 
    o rurales en las que son habituales los problemas de 
    contaminación atmosférica por el ozono en el nivel 
    superficial en escala local o regional. 

    Se  necesitan más investigaciones  en los sectores  en
los  que faltan  conocimientos y  en los  que  el  posible
impacto  mundial es elevado.  Incluyen ocho sectores  con-
cretos  de  futuras  investigaciones  y  evaluaciones  que
tienen  particular importancia para conocer y afrontar los
efectos  en  la  salud humana  de  la  pérdida  del  ozono

*   investigar  los  mecanismos  de la  inmunosupresión en
    modelos animales y en el hombre;

*   identificar  las  enfermedades  infecciosas  que  com-
    prenden una fase o proceso que puede empeorar  por  la
    exposición a la radiación UV-B y elaborar modelos para
    explicar esas enfermedades;

*   investigar  la dependencia respecto  a la longitud  de
    onda y obtener datos de dosis-respuesta para el hombre
    relativos  a los efectos de  la exposición a la  radi-
    ación  UV-B  sobre  la incidencia  de las enfermedades

*   determinar  el  efecto  de la  inmunosupresión  por la
    radiación UV-B sobre la eficacia de la vacunación;

*   aclarar  la función de los cambios inmunológicos en la
    inducción  de  melanomas  y de  cánceres cutáneos dis-
    tintos al melanoma por la radiación UV;

*   determinar  el  espectro  de acción  y  las relaciones
    dosis-efecto  para la inducción de  distintos tipos de
    melanoma por la radiación UV;

*   establecer  una definición mejor del  espectro de mec-
    anismos para la inducción del carcinoma escamocelular,
    y  en  particular  del carcinoma  basocelular,  por la
    radiación UV; e

*   investigar la biología y epidemiología de la catarata,
    y los métodos para reducir los riesgos de enfermedades

3.  Algunos  organismos recomiendan todavía el  empleo del
    CFC-11 y del CFC-12 como propulsores para la desinfec-
    ción  de aeronaves por pulverizaciones en aerosol.  Se
    necesitan urgentemente para ese uso nuevos propulsores
    que  no reduzcan el ozono, ininflamables, inocuos y no
    irritantes,  puesto que los antiguos gases propulsores
    están ya prohibidos en muchos países.

4.  Esnecesaria la cooperación internacional efectiva para
    reducir la futura pérdida del ozono estratosférico, lo
    que exige reducciones del 80%-90% por lo menos  en  la
    emisión  de clorofluorocarbonos reductores  del ozono.
    La  primera prioridad consiste en  hallar productos de
    sustitución y la segunda en elaborar procedimientos de
    evacuación  apropiados para los  actuales clorofluoro-
    carbonos  de  desecho.   Se recomienda  que  todos los
    países adopten medidas para reducir el empleo  de  los
    clorofluorocarbonos  con altas posibilidades de reduc-
    ción del ozono estratosférico.

    See Also:
       Toxicological Abbreviations