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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

    First draft prepared by D.T. Reisman,
    US Environmental Protection Agency, Cincinnati, USA

    World Health Orgnization
    Geneva, 1991

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    WHO Library Cataloguing in Publication Data


        (Environmental health criteria ; 120)

        1.Hydrocarbons, Chlorinated - adverse effects 2.Hydrocarbons,
        Chlorinated - toxicity  3.Environmental exposure 4.Environmental
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        ISSN 0250-863X

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1. SUMMARY         


    2.1. Identity        
    2.2. Physical and chemical properties    
        2.2.1. Physical properties     
        2.2.2. Chemical properties     
    2.3. Conversion factors  
    2.4. Analytical methods  
        2.4.1. Air     
        2.4.2. Water       
        2.4.3. Soil        
        2.4.4. Biological media    


    3.1. Natural occurrence  
    3.2. Man-made sources    
        3.2.1. Production levels and processes 
        3.2.2. Uses        
        3.2.3. Other sources of exposure   


    4.1. Overview        
    4.2. Transport and distribution between media    
        4.2.1. Air     
        4.2.2. Water       
        4.2.3. Soil        
    4.3. Biotransformation   
        4.3.1. Biodegradation  
        4.3.2. Bioconcentration, bioaccumulation, and biomagnification 
    4.4. Interactions with other physical and chemical factors   
        4.4.1. Phototransformation 
        4.4.2. Oxidation   
    4.5. Disposal and fate   


    5.1. Environmental levels    
        5.1.1. Air     
        5.1.2. Water       
        5.1.3. Soil        
        5.1.4. Food        
    5.2. General population exposure 
    5.3. Occupational exposure   


    6.1. Absorption, retention, distribution, metabolism, 
        elimination, and excretion  

        6.1.1. Oral        
        6.1.2. Inhalation  
        6.1.3. Dermal      
        6.1.4. Comparative studies 
        6.1.5.  In vitro studies    
    6.2. Metabolic transformation    
    6.3. Reaction with body components   


    7.1. Microorganisms      
    7.2. Aquatic organisms   
        7.2.1. Freshwater aquatic life 
        7.2.2. Marine and estuarine aquatic life   
    7.3. Terrestrial organisms and wildlife  
    7.4. Population and ecosystem effects    


    8.1. Acute toxicity studies  
        8.1.1. Acute oral, inhalation, and dermal toxicity 
        8.1.2. Eye and skin irritation 
    8.2. Short-term exposure 
        8.2.1. Oral        
        8.2.2. Short-term inhalation toxicity  
        8.2.3. Short-term dermal toxicity  
    8.3. Long-term exposure  
        8.3.1. Long-term oral toxicity 
        8.3.2. Long-term inhalation toxicity   
        8.3.3. Long-term dermal toxicity   
        8.3.4. Principal effects and target organs 
    8.4. Developmental and reproductive toxicity 
    8.5. Mutagenicity        
    8.6. Cell transformation 
    8.7. Carcinogenicity     


    9.1. General population exposure 
    9.2. Occupational exposure   
    9.3. Epidemiological studies 


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


    11.1. Conclusions     
    11.2. Recommendations for protection of human health and the 



APPENDIX 1          





Dr  K.  Abdo,  National  Institute of  Environmental Health
    Sciences,  Division of Toxicology Research and Testing,
    Research Triangle Park, North Carolina, USA

Professor  C.  Scott  Clark, Department  of  Environmental
    Health,  University  of  Cincinnati, Cincinnati,  Ohio,

Dr  S. Dobson, Institute of Terrestrial Ecology, Monks Wood
    Experimental Station, Abbots Ripton, Huntingdon, United

Dr  S.K.   Kashyap,  National  Institute   of  Occupational
    Health,  Indian  Council  of Medical  Research, Meghani
    Nagar, Ahmedabad, India

Dr  F.  Matsumura, Department of  Environmental Toxicology,
    University of California, Davis, California, USA

Mr  G.  Welter,  German  Federal  Environmental  Protection
    Agency, Berlin, Germany

Dr  J.  Withey,  Environmental and  Occupational Toxicology
    Division,   Environmental   Health   Centre,   Tunney's
    Pasture, Ottawa, Ontario, Canada  (Chairman)

Dr  Shou-zheng  Xue,  Department  of  Occupational  Health,
    School  of Public Health, Shanghai  Medical University,
    Shanghai, China


Dr  B.H.  Chen, International Programme on Chemical Safety,
    World    Health   Organization,   Geneva,   Switzerland

Mr  D.J.  Reisman,  Environmental  Criteria and  Assessment
    Office, US Environmental Protection Agency, Cincinnati,
    Ohio, USA  (Rapporteur)


    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  Chemical,  Palais  des  Nations,  1211  Geneva  10,
Switzerland (Telephone No. 7988400 or 7985850).


    A  WHO Task Group on Environmental Health Criteria for
Hexachlorocyclopentadiene  met in Cincinnati, USA, from 30
July to 3 August 1990.  Dr Chris DeRosa opened the meeting
on  behalf of the  US Environmental Protection  Agency  in
Cincinnati.   Dr B.H. Chen of  the International Programme
on  Chemical  Safety  (IPCS) welcomed  the participants on
behalf  of the Manager,  IPCS, and the  three  cooperating
organizations (UNEP/ILO/WHO).  The Task Group reviewed and
revised  the draft criteria  monograph and made  an evalu-
ation  of the risks for  human health and the  environment
from exposure to hexachlorocyclopentadiene.

    The first draft of this monograph was prepared  by  Mr
D.J.  Reisman of the  US Environmental Protection  Agency.
The second draft was also prepared by Mr  Reisman,  incor-
porating  comments  received following  the circulation of
the first draft to the IPCS contact points for Environmen-
tal Health Criteria Monographs. Dr B.H. Chen and  Dr  P.G.
Jenkins,  both  members of  the  IPCS Central  Unit,  were
responsible for the overall scientific content and techni-
cal editing, respectively.

    Financial  support for the meeting was provided by the
US Environmental Protection Agency in Cincinnati.

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


ACGIH       American Conference of Government Industrial Hygienists

BAF         bioaccumulation factor

BCF         bioconcentration factor

ECD         electron capture detection

GC          gas chromatography

HEX         hexachlorocyclopentadiene

LAQL        lowest analytically quantifiable level

LOAEL       lowest-observed-adverse-effect level

LOEL        lowest-observed-effect level

MS          mass spectrometry

NOAEL       no-observed-adverse-effect level

NOEL        no-observed-effect level

SD          standard deviation

TWA         time-weighted average


    Hexachlorocyclopentadiene (HEX) is a dense pale-yellow
or  greenish-yellow,  non-flammable  liquid with  a unique
pungent odour.  It has a relative molecular mass of 272.77
and low solubility in water.  HEX is highly  reactive  and
undergoes addition, substitution, and Diels-Alder reactions.

    In the USA, the Velsicol Chemical Corporation  is  the
only company that currently produces HEX.  In  Europe,  it
is  produced  by the  Shell  Chemical Corporation  in  the
Netherlands.   Production data are proprietary,  but it is
estimated  that between 3600  and 6800 tonnes of  HEX  are
produced  annually  in the  USA.  In 1988,  worldwide pro-
duction  was  approximately  15 000 tonnes  (BUA,   1988).
Although  HEX is used as an intermediate in the production
of many pesticides, some countries have restricted its use
in  the  production of  certain organochlorine pesticides.
It  is also used in  the manufacture of flame  retardants,
resins, and dyes.

    During  its manufacture and processing,  small amounts
of HEX are released into the environment. It may  also  be
released  when present as an impurity in some of the prod-
ucts for which it is an intermediate.  HEX may be released
both  during and after disposal.   Only limited monitoring
data  on the environmental  levels of HEX  are  available.
These  data suggest that  it is present  primarily in  the
aquatic  compartment and is  associated with bottom  sedi-
ments  and organic matter  except in locations  where dis-
posal  or release has occurred. In laboratory studies, HEX
readily sorbs to most types of soil  particles.   However,
leaching and movement in ground water have been reported.

    In  the USA, the total annual estimated release of HEX
into the environment is 5.9 tonnes (US EPA, 1989).  In the
Federal  Republic  of  Germany and  the Netherlands, about
400-500 kg  was emitted to  the atmosphere in  1987  (BUA,
1988).  Owing to the physical and chemical characteristics
of  HEX, only a small fraction of these emissions would be
expected to persist.

    Using  the  available  laboratory data,  the  fate and
transport  of HEX in the atmosphere have been modelled and
a  tropospheric  residence  time of  approximately 5 h has
been  calculated.  There have been  reports of atmospheric
transport  of HEX from an  area where waste is  stored and
from wet wells during the treatment of industrial wastes.

    In  water, HEX may undergo photolysis, hydrolysis, and
biodegradation.  In  shallow  water, it  has  a photolytic
half-life of < 1 h.  In deeper water where  photolysis  is
precluded,  the  hydrolytic  half-life has  been  found to
range  from several days to  approximately 3 months, while
biodegradation  is predicted to occur more slowly.  HEX is

known  to volatilize from surface water, the rate of vola-
tilization  being affected by  turbulence and by  sorption
onto sediments.

    Owing  to its low solubility  in water, HEX should  be
relatively immobile in soil. However, HEX has  been  found
in  ground water.  Volatilization, which is most likely to
occur  at the soil  surface, is inversely  related to  the
levels  of organic matter in the soil. The results of lab-
oratory  studies  indicate  that chemical  hydrolysis  and
microbial metabolism, both aerobic and anaerobic, would be
expected to reduce HEX levels in soils.

    The biomagnification potential of HEX should theoreti-
cally  be  substantial  because of  its high lipophilicity
(log  octanol/water partition coefficient).  However, this
has  not been supported by experimental evidence.  Studies
in  laboratory animals have  shown that 14C-HEX    is both
metabolized  and excreted within the first few hours after
oral  dosing,  with little  being  retained in  the  body.
Steady-state  bioconcentration  factors in  fish are < 30.
Bioaccumulation factors derived from short-term model eco-
systems indicate a moderate accumulation potential. There-
fore,  it would appear that HEX and its metabolites do not
persist  or accumulate to  any great extent  in biological

    Low  concentrations of HEX have been shown to be toxic
to aquatic life. Lethality in acute exposures (48 to 96 h)
has  been  observed in  both  freshwater and  marine crus-
taceans  and fish at  nominal concentrations of  32-180 µg
per  litre in static exposure  systems in which the  water
was  not renewed during  the test.  Since  the  photolytic
half-life  is  < 1 h,  the HEX  concentration  would  have
decreased substantially during the exposure period used in
these studies. In the only studies using flowing water and
measured  HEX concentrations, 96-h  LC50   values of  7 µg
per  litre were  obtained for  the fathead  minnow  and  a
marine shrimp. Tests with these two species yielded values
for LC10 of 3.7 and LC40 of 0.7 µg/litre, respectively.

    Seven-day  static  tests  with marine  algae  showed a
median  reduction  of  growth (EC50)    at nominal concen-
trations ranging from 3.5-100 µg/litre,   depending on the

    In  aqueous media, HEX is toxic to many microorganisms
at  nominal concentrations of 0.2-10 mg/litre, i.e. levels
substantially  higher  than  those  needed  to  kill  most
aquatic animals or plants.  HEX appears to be  less  toxic
to  microorganisms in soil than in aquatic media, probably
because of adsorption of HEX on the soil matrix.

    Although exposure would be expected to be  low,  there
is  insufficient information currently available to deter-
mine the effects of HEX exposure on terrestrial vegetation
or wildlife.

    The  absorption of unchanged  HEX is minimized  by its
reactivity  with body membranes and tissues and especially
with  the  contents  of the  gastrointestinal tract.  Most
radiolabelled 14C-HEX   is retained by the kidneys, liver,
trachea, and lungs of animals after oral, dermal, or inha-
lation  dosing.  Absorbed HEX  is metabolized and  rapidly
excreted,  predominantly in the urine, less in the faeces,
and < 1% in expired air.  The terminal elimination time is
about  30 h, irrespective of the  route of administration.
After   inhalation   or  intravenous   administration,  no
unchanged HEX is excreted; the faecal and  urinary  metab-
olites have been isolated but not identified.  The failure
to  identify metabolites represents a  major difficulty in
assessing the pharmacokinetics and potential mechanisms of
HEX action.

    The acute inhalation LC50   (over a period of approxi-
mately  4 h) is 17.9 mg/m3 in male rats and  39.1 mg/m3 in
females.  Although there are some interspecies differences
between  guinea-pigs, rabbits, rats, and  mice, HEX vapour
is highly toxic to all tested species.  It appears  to  be
most  toxic when administered  by inhalation, as  compared
with  oral and dermal administration, and is a severe pri-
mary  irritant.  The systemic  effects of acute  exposure,
irrespective  of  the  route  of  administration,  include
pathological  changes  in  the lungs,  liver, kidneys, and
adrenal glands.

    Short-term  oral dosing of rats (38 mg/kg per day) and
mice (75 mg/kg per day) for 91 days produced nephrosis and
inflammation and hyperplasia of the forestomach.  No overt
signs were noted when mice or rats were exposed  by  inha-
lation to 2.26 mg/m3 (0.2 ppm),  6 h/day, 5 days/week, for
14 weeks.  At 1.69 mg/m3   (0.15 ppm) only mild irritation
was seen. Inhalation exposure of rats to 5.65 mg/m3   (0.5
ppm)  for 30 weeks caused histopathological changes in the
liver,  respiratory tract, and kidneys. A short-term inha-
lation  study of HEX in  mice and rats for  90 days showed
respiratory  system  effects at  4.52 mg/m3   (0.4 ppm) or
more. HEX has not been shown to be a mutagen  in  in  vitro
assays,   either with or without  metabolic activation. It
was  also inactive in mouse dominant lethal assays. It has
not  been shown to be a teratogen in rats and mice by oral
exposure;  there are no data for the teratogenicity of HEX
after inhalation exposure.

    Only  limited data are  available on the  human health
effects  of HEX exposure.  There have been  isolated inci-
dents in which HEX caused severe irritation in  the  eyes,
nose,  throat, and lungs.   The irritation was  usually of
short  duration,  with  recovery beginning  after exposure
ceased.  There  were no  statistically significant differ-
ences in certain liver enzymes between exposed and control
groups  after  short-term  exposure.  The  long-term human
health  effects  of  continuous low-level  exposure and/or

intermittent acute exposure are not known. Handlers of the
product and its waste, as well as sewage workers and resi-
dents near disposal sites, have been shown to be  at  risk
because of the potential for exposure to the  chemical  or
wastes from its manufacture.

    The data base is not extensive or adequate  to  assess
the  carcinogenicity of HEX.   The US National  Toxicology
Program  (NTP) has conducted a  lifetime animal inhalation
bioassay  using both rats  and mice.  After  the pathology
report  has been produced, there  will be a better  under-
standing  of the long-term  effects of HEX  exposure.   An
assessment  of  carcinogenicity  will have  to be deferred
until  the results of the NTP bioassay are available.  The
International  Agency for Research on Cancer evaluated the
existing  data for HEX and classified it in Group 3 (which
indicates  that because of major qualitative or quantitat-
ive  limitations,  the  studies cannot  be  interpreted as
showing either the presence or absence of  a  carcinogenic
effect). Several epidemiological studies were cited in the
literature; there were no reports of an increase, attribu-
table  to HEX or its metabolites, in the incidence of neo-
plasms at any site.


2.1.  Identity

    Hexachlorocyclopentadiene  (HEX) is the  most commonly
used  name for the compound that is designated 1,2,3,4,5,5'-
hexachloro-1,3-cyclopentadiene  by the International Union
of Pure and Applied Chemistry (IUPAC).

Chemical formula:   C5Cl6

Chemical Structure

CAS and IUPAC   1,2,3,4,5,5'-hexachloro-1,3-cyclo-
name:           pentadiene

Synonyms and    Hexachlorocyclopentadiene, perchloro-
common trade    cyclopentadiene, hexachloro-1,3-cyclo-
names:          pentadiene, HEX, HCPD, HCCP,
                HCCPD, C-56, HRS 1655, Graphlox

CAS registry number:    77-47-4

RTECS number:   GY 1225000

CIS accession number:   7800117

EINECS number:  2010293

2.2.  Physical and chemical properties

2.2.1.  Physical properties

    Hexachlorocyclopentadiene   (98%  pure)  is   a  dense
liquid  with  low solubility  in  water (Table 1).  It  is
non-flammable  and  has  a  characteristic  pungent  musty
odour.   The pure compound is a light lemon-yellow colour,
but  impure HEX may have a greenish tinge (Stevens, 1979).
HEX  (and quite possibly other substances) was reported to
have  created a  blue haze  in an  accident involving  the
treatment of waste (Kominsky et al., 1980). A list of some
physical  and chemical properties is presented in Table 1.
It  appears that the compound is strongly adsorbed to soil

colloids.   In spite of its  low vapour pressure and  high
boiling point, HEX volatilizes rapidly from water (Atallah
et al., 1980).  According to the Handbook of Chemistry and
Physics  (Weast  &  Astle, 1980),  the ultraviolet-visible
lambdamax in heptane is 323 nm with a log molar absorptivity
of  3.2.  This absorption  band extends into  the  visible
spectrum,  as shown by the  yellow colour of HEX.   Facile
homopolar  carbon-chlorine bond scission might be expected
in  sunlight  or  under fluorescent  light.   The infrared
spectrum  has characteristic absorptions at 6.2, 8.1, 8.4,
8.8,  12.4, 14.1, and 14.7 µm.    The mass spectrum of HEX
shows  a  weak molecular  ion (M) at  M/e 270, but  a very
intense  M-35  ion, making  this  latter ion  suitable for
sensitive specific ion monitoring.
Table 1.  Physical and chemical properties of hexachlorocyclopentadiene
Property                       Value/description    Reference
Relative molecular mass        272.77               Stevens (1979)

Physical state (25 °C)         pale yellow liquid   Hawley (1977)

Odour                          pungent              Hawley (1977)

Electronic absorption maximum  322 nm               Wolfe et al. (1982)
(in 50% acetonitrile-water)    (log e = 3.18)

Solubility (22 °C)
   Water (mg/litre)            1.03-1.25            Chou & Griffin (1983)

   Organic solvents            miscible (hexane)    Bell et al. (1978)

Vapour density (air = 1)       9.42                 Verschueren (1977)

Vapour pressure
   (25 °C)                     10.7 Pa (0.08 mmHg)  Irish (1963)
   (25 °C)                     10.7 Pa (0.08 mmHg)  Wolfe et al. (1982)
   (62 °C)                     131 Pa (0.98 mmHg)   Stevens (1979)

Relative density               1.717 (15 °C)        Hawley (1977)
                               1.710 (20 °C)        Stevens (1979)
                               1.702 (25 °C)        Weast & Astle (1980)

Melting point (°C)             -9.6                 Hawley (1977)
                               -11.34               Stevens (1979)

Boiling point (°C)             239 at 103 kPa       Hawley (1977);
                               (753 mmHg)           Stevens (1979)
                               234                  Irish (1963)

Table 1 (contd.)
Property                       Value/description    Reference
Octanol/water partition
 coefficient (log Pow)
   (measured):                 5.04 ± 0.04          Wolfe et al. (1982)
                               (at 28 °C)a
   (estimated):                5.51                 Wolfe et al. (1982)

   (measured):                 5.51b                Veith et al. (1979)

Octanol/water partition        1.1 (± 0.1) x 105    Wolfe et al. (1982)
 coefficient (Pow) (28 °C)

Latent heat of vaporization    176.6 J/g            Stevens (1979)

a   Measured by simple partition.
b   Measured by HPLC.
2.2.2.  Chemical properties

    Hexachlorocyclopentadiene  is a highly  reactive diene
that readily undergoes addition and substitution reactions
and  also participates in Diels-Alder reactions (Ungnade &
McBee, 1958).  The products of the Diels-Alder reaction of
HEX  with  a  compound containing  a non-conjugated double
bond  are generally 1:1 adducts containing a hexachlorobi-
cyclo(2,2,1)heptene structure; the monoene derived part of
the  adduct is nearly  always in the  endoposition, rather
than the exoposition (Stevens, 1979).

    Two  excellent early reviews  of the chemistry  of HEX
were  produced  by  Roberts  (1958)  and  Ungnade  & McBee
(1958).  Look (1974) reviewed the formation of HEX adducts
of  aromatic compounds and  the by-products of  the Diels-
Alder reaction.

2.3.  Conversion factors

    1 ppm = 11.3 mg/m3        1 mg/m3 = 0.088 ppm

2.4.  Analytical methods

2.4.1.  Air

    The techniques used to collect samples of  HEX  vapour
in  air involve the  adsorption and concentration  of  the
vapour  in liquid-filled impingers or solid sorbent-packed

    Whitmore et al. (1977) pumped airborne vapours through
a  miniature  glass  impinger tube  containing  hexane  or
benzene   and   through   a  solid   sorbent-packed   tube

(Chromosorb(R) 102) tube. Sampling efficiency was found to
be  97% with hexane and  100% with benzene.  The  sampling
efficiency for the solid sorbent tube was 100%. The sensi-
tivity  of the  liquid impinger  system was  found  to  be
< 11.2 µg/m3 (< 1 ppb) in ambient air.

    Kominsky  &  Wisseman  (1978) collected  HEX vapour on
Chromosorb(R) 102 (20/40 mesh) sorbent previously  cleaned
by  extraction with 1:1 acetone/methanol solvent to remove
interfering compounds. HEX was desorbed with carbon disul-
fide  (68% efficiency) and analysed by gas chromatography-
flame ionization detection (Neumeister & Kurimo, 1978).

    Dillon  (1980) and Boyd  et al. (1981)  developed  and
validated  sampling and analytical methods for air samples
containing HEX.  Methods were reliable at levels below the
8-h  time-weighted average (TWA) and threshold limit value
(TLV)  of 0.1 mg/m3   recommended by  the American Confer-
ence of Governmental Industrial Hygienists (ACGIH).

    The  method developed by NIOSH,  Physical and Chemical
Analytical  Method No. 308 (NIOSH,  1979), used adsorption
on Porapak(R) T (80/100 mesh), desorption with hexane (100%
for 30 ng HEX on 50-100 mg adsorbent), and  then  analysis
by  GC-63Ni   electron capture detection (ECD).  The solid
sorbent was cleaned by soxhlet extraction with  4:1  (v/v)
acetone/methanol  (4 h)  and  hexane (4 h)  and  was dried
under vacuum overnight at 50-70 °C to ambient temperature.
The  pyrex sampling tubes  (7 cm long, 6 mm  outside diam-
eter,  4 mm inside diameter)  contained a 75-mg  layer  of
sorbent in the front and a 25-mg section in the back. Each
section  was held  in place  by two  silylated glass  wool
plugs.   A 5-mm long airspace was needed between the front
and back sections. A battery-operated sampling pump, which
drew  air at 0.05 and 2.0 litre/min, was used for personal
sampling of workers.  The lowest analytically quantifiable
level  was 25 ng HEX/sorbent sample (using 1 ml of hexane-
desorbing solvent and a 1-h period of desorption by ultra-
sonification),  and  the  upper limit  was 2500 ng/sorbent
sample.  The  method was  validated  for air  HEX  concen-
trations that were between 13 and 865 µg/m3    at 25-28 °C
and with a relative humidity of 90% or more.

    Gas  chromatography has been considered  the preferred
method for analysing HEX in air, using either flame ioniz-
ation  collection or electron capture  detection (Whitmore
et  al., 1977; Neumeister &  Kurimo, 1978; Chopra et  al.,
1978;  NIOSH, 1979).  Gas chromatography/mass spectroscopy
(GC/MS) is necessary for confirmation (Eichler, 1978).

    Gas chromatography with electron capture detection has
been  reported to be  the most sensitive  analytical tech-
nique for HEX.  The chromatographic response was stated to
be a linear and reproducible function of HEX concentration

over the range from approximately 5 to  142 ng/ml  (25-710
pg injected), with a correlation coefficient of 0.9993 for
peak height measurement (NIOSH, 1979).

    The  lowest analytically quantifiable level  (LAQL) of
HEX in air was found to be 25 ng/sorbent tube.  This level
represented  the  smallest amount  of  HEX that  could  be
determined with a recovery of > 80% and a  coefficient  of
variation of < 10%.  The desorption efficiency of 100% was
obtained  by averaging the  levels ranging from  near  the
LAQL of 25 ng to 1000 times the LAQL (NIOSH, 1979).

2.4.2.  Water

    Since  HEX is sensitive to  light in both organic  and
aqueous  solutions, the water samples, extracts, and stan-
dard  HEX solutions to be used for laboratory examinations
must  be protected from  light.  The rate  of  degradation
depends on the light intensity and wavelength,  the  half-
life of HEX being approximately 7 days when  the  solution
is  exposed to ordinary lighting conditions in the labora-
tory (Benoit & Williams, 1981). Storing the HEX-containing
solutions  in amber- or red-coloured (low  actinic) glass-
ware  is  recommended  for adequate  protection  (Benoit &
Williams, 1981).

    XAD-2  resin extraction has  been used to  concentrate
HEX  from large volumes  of water.  Solvent  extraction of
water has also proved successful. The detection limit used
for the organic solvent extraction technique was 50 ng per
litre,  as opposed to  0.5 ng/litre for the  XAD-2 method.
When  the solvent extraction method was used under subdued
lighting  conditions in the laboratory,  the efficiency of
recovery for an artificially loaded water sample was found
to  be 79-88%.  The authors concluded that the XAD-2 resin
could  not  be  used  to  sample  accurately  quantitative
amounts  of HEX in water,  but it could be  used to screen
samples  qualitatively because of the  low detection limit
(Benoit & Williams, 1981).

    Lichtenberg  et al. (1987)  developed methods for  the
sampling  and  analysis  of organic  pollutants, including
HEX, in water for the US Environmental  Protection  Agency
(US EPA). Their emphasis was on compound-specific methods,
such as GC/MS employing packed and capillary columns.  For
organochlorine pesticides, methylene chlorine in hexane is
used for extraction.

    Thielen  et al. (1987) developed a technique combining
microextraction  and  capillary column  gas chromatography
and applied it to plant discharge streams  for  repetitive
waste-water  discharge permit analyses. Samples  were col-
lected in amber bottles and sealed with Teflon-lined caps.
Hewlett-Packard 5880   gas  chromatographs  equipped  with
flame  ionization  detectors, electron  capture detectors,

and  7672A autosamplers were used for analyses.  According
to  the researchers, the  overall effect of  converting to
the  microextraction/capillary-column  procedure was  both
cost-and  time-saving, and instrumentation needs  were cut
by half.  A statistical comparison was made  to  determine
whether  this  technique was  equivalent to purge-2nd-trap
and  normal  extraction methods.  It  was found  that  the
differences   in  precision  were  not  significant  above
2 µg/litre.     However, the precision and accuracy of the
microextraction  method  was poor  for  HEX owing  to  its
instability  and the fact  that it is  adsorbed onto  sur-
faces.   The final microextraction data yielded an average
HEX recovery (for 44 samples) of 99.27% (S.D. 18.94).

2.4.3.  Soil

    DeLeon et al. (1980a) developed a method for determin-
ing volatile and semi-volatile organochlorine compounds in
samples taken from the soil and from  chemical  waste-dis-
posal  sites. This method used  hexane extraction followed
by  analysis of the extract with temperature-programmed GC
on  high-resolution  glass  capillary columns  using  ECD.
GC/MS was used to confirm the presence of  the  chlorocar-
bons.  The lowest detection limit was 10 µg/g.

2.4.4.  Biological media

    A method to determine levels of HEX in blood and urine
has  been described by DeLeon et al. (1980b).  This method
involves isolation of the compound from the blood or urine
sample  by liquid-liquid extraction, GC analysis with ECD,
and  confirmation by GC/MS.  The best recoveries have been
obtained  by using a toluene-acetonitrile  extraction mix-
ture for blood assays and a petroleum ether extraction for
urine assays.  In this method, the detection limits of HEX
were 50 ng/ml for blood and 10 ng/ml for urine. Studies by
the  Velsicol Chemical Corporation  have shown that  up to
30%  of the HEX  can be lost  if the extracts  are concen-
trated  to 0.1 ml.  Quantitative recovery is possible only
for  volumes  of  concentrate larger  than  0.5 ml,  which
limits the sensitivity of the DeLeon method. However, this
method  may offer a sensitive process for monitoring occu-
pational exposure.

    The Velsicol Chemical Corporation (1979) has developed
three  analytical methods, which have been used for urine,
fish fillet, beef liver, beef skeletal muscle,  beef  adi-
pose  tissue, beef kidney, chicken liver, chicken skeletal
muscle,  and chicken adipose tissue. The respective recov-
eries   were:   80 ± 10%  (1-50 ppb),   81 ± 1%,  69 ± 4%,
88 ± 2%,  86 ± 5%, 71 ± 3%, 55 ± 9%, 76 ± 4%, and 85 ± 2%.
The limit of detection for HEX was 0.5 ppb.


3.1.  Natural occurrence

    HEX  is  not  found as  a  natural  component  in  the

3.2.  Man-made sources

    Low  levels of HEX  are released into  the environment
during  its  manufacture  and during  the  manufacture  of
products  requiring HEX (US EPA, 1980c).  It is also found
as  an  impurity and  a  degradation product  in compounds
manufactured from HEX (Spehar et al., 1977; Chopra et al.,

3.2.1.  Production levels and processes

    Since there is only one producer of HEX in the USA and
one  in Europe (in the Netherlands), production statistics
are considered to be confidential business information and
are not available to the public.  Production estimates for
HEX  based  on  the manufacture  of chlorinated cyclodiene
pesticides  in the early  1970s were approximately  22 700
tonnes/year  (Lu et al.,  1975).  After restrictions  were
established for the use of some pesticides  produced  from
HEX, USA production estimates were lowered to a  range  of
3600-6800 tonnes/year  (US EPA, 1977).  In 1988, worldwide
production volume was estimated to be approximately 15 000
tonnes (BUA, 1988).

    Commercial  HEX has various purities  depending on the
method  of  synthesis.  HEX  made  by the  chlorination of
cyclopentadiene  by  alkaline hypochlorite  at 40 °C, fol-
lowed  by fractional distillation,  is only 75%  pure, and
contains many lower chlorinated cyclopentadienes and other
contaminants (e.g., hexachlorobenzene and octachlorocyclo-
pentene). Purities above 90% have been obtained by thermal
dechlorination  of  octachlorocyclopentene  at  470-480 °C
(Stevens,   1979).   The  current  specification  for  HEX
produced  by the Velsicol Chemical Corporation at Memphis,
Tennessee, USA, which is used internally and sold to other
users,  has  a minimum  purity  of 97%  (Velsicol Chemical
Corporation, 1984).

    The  nature and levels  of HEX contaminants  vary with
the  method of production. The major contaminants found in
an  industrial  preparation  of HEX  (from  Velsicol) were
octachlorocyclopentene  (0.68%),  hexachloro-1,3-butadiene
(1.11%),   tetrachloroethane   (0.09%),  hexachlorobenzene
(0.04%),  and  pentachlorobenzene  (0.02%). Another  prep-
aration  (from Shell International Petroleum in 1982) con-
tained  up to 1.5% of  octachlorocyclopentene and approxi-
mately 0.2% of hexachloro-1,3-butadiene (BUA, 1988).

3.2.2.  Uses

    HEX is the key intermediate in the manufacture of some
chlorinated  cyclodiene pesticides (Fig. 1).  These pesti-
cides  include  heptachlor,  chlordane, aldrin,  dieldrin,
endrin,  mirex, pentac, and endosulfan.  Another major use
of  HEX is in the manufacture of flame retardants, such as
chlorendic  anhydride, and Dechlorane  Plus.  It has  been
estimated  that  the  production volume  is  split equally
between fire retardant and pesticide use (BUA, 1988).  HEX
is  also used, to a  lesser extent, in the  manufacture of
resins and dyes (US EPA, 1980b), and was  previously  used
as a general biocide (Cole, 1954).

3.2.3.  Other sources of exposure

    Human  and environmental exposure to  HEX has occurred
as  a  result of  releases  at production  and  processing
facilities,  during transport to disposal  facilities, and
at land disposal sites.

    In  1977,  a  waste transporter  released an estimated
5.5 tonnes   of  HEX  and  octachlorocyclopentene,  a  co-
contaminant,  into  the  sewers of  Louisville,  Kentucky,
which  led to the contamination of several miles of sewer.
The  waste-water  treatment  plant was  temporarily closed
because of excessive exposure of workers to HEX. (Kominsky
& Wisseman, 1978; Morse et al., 1978, 1979). Releases from
the  Memphis  production  facility have  resulted  in high
concentrations of HEX in waste water from the facility and
have  led  to  HEX being  present  in  the inflow  to  the
receiving  waste-water treatment plant  and in air  at the
treatment  plant.  HEX has also been released from a waste
site in Montague, Michigan, USA (US EPA, 1980b).

    The US EPA Toxic Chemical Release Inventory  for  1987
revealed that over 4.5 tonnes of HEX was released  at  the
Velsicol facility in Marshall, Illinois, USA (most  of  it
from underground injection disposal), that over 540 kg was
released at the Velsicol facility in Memphis, and  that  a
similar quantity was released from the Occidental Chemical
Corporation  at Niagara Falls,  New York, USA.  The latter
two releases were primarily to the air (US EPA, 1989).



4.1.  Overviewa

    The  fate and transport of  HEX in the atmosphere  are
not   well  understood,  but  the   available  information
suggests  that the compound does not persist.  Atmospheric
transport  of HEX from  an area of  stored waste has  been
reported  (Peters  et al.,  1981).  Experimentally derived
constants  for HEX in various  environmental processes are
given in Table 2.

Table 2.  Summary of constants used in the exposure 
analysis modelling system (EXAMS)a
Constants                    Values used
Water solubility (Ks)        1.8 mg/litre

Henry's law constant (KH)    2.7 x 10-2 atm m3/mol

Octanol/water partition      1.1 x 105
 coefficient (Pow)

Photolysis (kp)              3.9 h-1

Hydrolysis                   4.0 x 10-3 h-1b

Oxidation (kox)              1 x 10-10 M-1 sec-1c

Biodegradation (kB)          1 x 10-5 ml org-1 h-1d
a   Adapted from Wolfe et al. (1982).
b   Extrapolated to 25 °C.
c   Estimated value (Wolfe et al., 1982).
d   This is a maximum value based on the observation 
    that there was no detectable difference in the 
    hydrolysis rate in either sterile or non-sterile 
    studies and measured organism numbers (plate 

    In  water, HEX probably dissipates rapidly by means of
photolysis,  hydrolysis,  and biodegradation.   In shallow
water  (a few centimetres deep), it has a photolytic half-
life of approximately 0.2 h (Butz et al., 1982;  Wolfe  et
al.,  1982).  Chou et  al.  (1987) found  this first-order
reaction  to take  even less  time in  full sunlight.   In
deeper water where photolysis is precluded, hydrolysis and
biodegradation should become the key degradative processes
when  there is little movement  in the system. The  hydro-
lytic  half-life  of  HEX  ranges  from  several  days  to

a   Throughout this chapter, the terms sorb and sorption 
    are used in preference to absorb/adsorb and 

approximately 3 months, and it is not strongly affected by
the pH in the environmental range (5-9), by salinity or by
the  presence of suspended  solids (Yu &  Atallah,  1977a;
Wolfe et al., 1982). HEX is known to volatilize from water
(Kilzer et al., 1979; Weber, 1979).  It is  probable  that
volatilization  is  limited  by diffusion,  i.e. loss from
deeper  waters  should  occur very  slowly unless vertical
mixing  has taken place.   Sorption on sediments  may also
retard volatilization.

    The fate and transport of HEX in soils are affected by
its  strong tendency to  sorb onto organic  matter (Weber,
1979;  Kenaga & Goring, 1980; Wolfe et al., 1982). Another
possibility is that HEX partitions to the interior of soil
particles  and stays  in loams  and silt  in  a  dissolved
state.   HEX should be relatively immobile in soil because
of  its high log P value (Briggs, 1973), but several inci-
dents in the USA have shown that this is not true  in  all
soil  types  (Sprinkle,  1978).  Volatilization,  which is
likely   to  occur  primarily  at  the  soil  surface,  is
inversely related to the organic matter level  and  water-
holding capacity of the soil (Kilzer et al., 1979). Leach-
ing  of HEX  by ground  water can  occur,  while  chemical
hydrolysis  and microbial metabolism would  be expected to
reduce  levels in the environment. HEX is metabolized by a
number   of   unidentified  soil   microorganisms  (Rieck,
1977b,c; Thuma et al., 1978).

    The  high lipophilicity and log Pow of  HEX indicate a
high potential for bioaccumulation.  However, in practice,
this potential is not realized because of  metabolism  and
elimination.  Steady-state bioconcentration factors (BCFs)
in fish measured in 30-day flow-through systems were 29 or
less (Spehar et al., 1979; Veith et al., 1979). In a model
ecosystem  study, BCF values for a range of aquatic organ-
isms were between 340 and 1600. These measurements did not
distinguish   between   the   parent  compound   and   the
metabolites  and, therefore, should  be regarded as  over-
estimates of bioaccumulation.

4.2.  Transport and distribution between media

4.2.1.  Air

    Little  relevant  information is  available to predict
the fate of HEX in the air.  Cupitt (1980)  estimated  its
tropospheric residence time to be approximately 5 h, based
on   estimated  rates  of  reaction  with  photochemically
produced  hydroxyl  radicals  and ozone.   The theoretical
reaction  rates  were  calculated to  be  59 x 10-12   and
8 x 10-18    cm3   molecule-1   sec-1,   respectively.  In
estimating  the tropospheric residence  time, or the  time
for  a quantity of HEX  to be reduced to  1/e (or approxi-
mately 37%) of its original value, it was assumed that the
rate  constants  calculated  at room  temperature for both
reactions were valid in the ambient atmosphere,  and  that
the  background  concentrations  of hydroxyl  radical  and

ozone were 106   and 1012   molecules cm3,   respectively.
Direct  atmospheric photolysis of  HEX was also  rated  as
"probable",  since  HEX  has   a  chromophore that absorbs
light in the solar spectral region, and is known to photo-
lyse  in aqueous media.  No attempt was made to estimate a
rate for atmospheric photolysis.  Cupitt (1980) listed the
theoretical degradation products as phosgene, diacylchlor-
ides,  ketones, and free  chlorine radicals, all  of which
would  be  likely  to  react  with  other   elements   and

    The  vapour pressure and  vapour density, water  solu-
bility,  sorption  properties, rapid  photolysis (Wolfe et
al., 1982), and high reactivity (Callahan et al., 1979) of
HEX  are significant factors  that affect its  atmospheric
transport.  The atmospheric transport of HEX vapour from a
closed waste site in Montague, Michigan, USA, was reported
by  Peters  et al.  (1981).   At an  unspecified  distance
downwind  from the site,  HEX was detected  in the air  at
concentrations  of  0.36-0.59 µg/m3     (0.032-0.053 ppb).
Based on the concentration ratio of HEX and a  tracer  gas
released  at a known rate,  the average HEX emission  rate
during  the  measurement  period  was  calculated  to   be
0.26 g/h.

4.2.2.  Water

    In the event of release into shallow or flowing bodies
of water, degradative processes such as photolysis, hydro-
lysis,  and biodegradation, as well as transport processes
involving  volatilization and other physical  loss mechan-
isms,  would be  expected to  play a  significant role  in
dissipating  HEX. In deeper, non-flowing  bodies of water,
hydrolysis  and biodegradation may become  the predominant
processes in determining the fate of HEX.

    HEX introduced into bodies of water may be transported
in either the undissolved, dissolved, or sorbed forms.  In
its undissolved form, HEX will tend to sink because of its
high relative density, and it may then become concentrated
in deeper waters where photolysis and volatilization would
be precluded.  Some HEX may be dissolved in water  (up  to
approximately 2 mg/litre) and then be dispersed with water
flow. The solubility of HEX in water, soil  extracts,  and
sanitary  landfill leachates ranges  from 1.03 to  1.25 mg
per litre (Chou & Griffin, 1983).  It tends to  sorb  onto
organic matter and may then be transported with water flow
in  a suspended form.  Transport  to the air may  occur by
volatilization,  which  has  been measured  in  laboratory
studies  (Kilzer et al., 1979;  Weber, 1979) and was  pre-
dicted  using the EXAMS model by Wolfe et al. (1982). How-
ever,  suspended solids in  surface water may  be a  major
factor in reducing volatilization.

    The  photodegradation and degradation products  of HEX
in  aqueous solution have  been studied in  the laboratory
(Chou & Griffin, 1983; Chou et al., 1987).   When  aqueous

solutions  containing  1.33 µg    HEX/ml (a  concentration
below its solubility in water) were exposed  to  sunlight,
the  rate of photodegradation followed a first-order reac-
tion;  the photolytical half-lives  of HEX in  tap  water,
creek water, and distilled water in sunlight were all less
than 4 min. At least eight degradation products were posi-
tively or tentatively identified, 2,3,4,4,5-pentachloro-2-
cyclopentenone,   hexachloro-2-cyclopentenone,  and  hexa-
chloro-3-cyclopentenone being the primary photodegradation
products.  Secondary  degradation products  and other com-
pounds were formed through minor routes of degradation.

    A proposed pathway for aqueous degradation is shown in
Fig. 2 (Chou & Griffin, 1983).


    Kilzer  et al. (1979) determined the rate  of  14C-HEX
volatilization  from water as  a function of  the rate  of
water  evaporation.  Bottles  containing aqueous  HEX sol-
utions (50 µg/litre)   were kept at 25 °C without shaking.
The  escaping vapour  condensed on a "cold finger" and was
quantified by liquid scintillation spectroscopy.  Based on
recovery  of added label, the HEX volatilization rates for
the first and second hours of testing were  calculated  to
be  5.87 and 0.75%/ml  of water, respectively.   Since the
water  evaporation rate was 0.8-1.5 ml/h,  the evaporation
rates for HEX were within the ranges of 4.7-8.8  and  0.6-
1.1%/h, respectively.  These results suggest that a fairly
rapid  initial volatilization occurred  at the water  sur-
face,  and that by the second hour diffusion of HEX to the
water surface may have been limiting because of the static
conditions of the test.  If the rate observed  during  the
second  hour  had continued  for  the remaining  24 h, the
total  loss  would  have been  approximately  18-34%, i.e.
somewhat  less than that observed in the test conducted by
Weber (1979) where unstoppered bottles were shaken.

    At  25-30 °C and in the environmental pH range of 5-9,
the hydrolytic half-life of HEX was found to  be  approxi-
mately  3-11 days  (Yu &  Atallah,  1977a; Wolfe  et  al.,
1982).  In a later study  in which evaporation and  photo-
chemical  reactions  were carefully  prevented, the hydro-
lytic   half-life  was  approximately  3 months   (Chou  &
Griffin, 1983).  Hydrolysis is much slower than photolysis
(see  Table 2)  but  may be  a  significant  load-reducing
process  in waters where photolysis and physical transport
processes  are  not  important (i.e.  in deep, non-flowing
waters).  Wolfe et al. (1982) found HEX hydrolysis  to  be
independent of pH over the range of 3-10.  The  rate  con-
stant  was dependent  on temperature  at pH  7.0, and  the
half-life was estimated to be 3.31, 1.71, and 0.64 days at
30,  40, and 50 °C, respectively.  The addition of various
buffers  or sodium chloride (0.5 mol/litre) did not affect
the  hydrolysis  rate  constant, suggesting  that the rate
constant  obtained would be applicable  to marine environ-
ments  as well. The  addition of natural  sediments,  suf-
ficient to sorb up to 92% of the compound, caused the rate
constant  to vary  by less  than a  factor of  2.  It  was
therefore  concluded that sorption to  sediments would not
significantly affect the rate of hydrolysis (Wolfe et al.,

4.2.3.  Soil

    When  it is released on to soil, HEX is likely to sorb
strongly  to any organic  matter or humus  present (Weber,
1979;  Kenaga  &  Goring, 1980).   The  HEX concentrations
should  decrease with time  as populations of  soil micro-
organisms  that  are  better  adapted  to  metabolize  HEX
increase  (Rieck, 1977b,c; Thuma et al., 1978). Volatiliz-
ation, photolysis, and various chemical processes may also
dissipate the compound in certain soil environments.

    The main methods of transport for HEX applied  to  the
soil  are  (a) the  movement of particles  to which it  is
sorbed  and  (b) volatilization.   Other possibilities are
that  HEX is sorbed  on to soil  colloids or that  it par-
titions  to the interior  of soil particles  and stays  in
loams  and silts in a dissolved state.  No data are avail-
able pertaining to HEX transport on soil  particles.  How-
ever,  in a few studies,  the rate of volatilization  from
soils  has been reported and is discussed in the following

    Kilzer  et  al. (1979)  found  that 14C-HEX    and its
degradation  products volatilized from moist  soils (sand,
loam, and humus) at a faster rate during the first hour of
the study than during the second hour. HEX (50 µg/kg)  was
placed  in bottles with each  soil type, the bottles  were
shaken vigorously, and they were then incubated for 2 h at
25 °C without shaking.  The radiolabelled HEX condensed on
a  "cold finger"  and  was  quantified by  liquid scintil-
lation counting. For sand, loam, and humus, the volatiliz-
ation  rate was expressed  as the percentages  of  applied
radioactivity per ml of evaporated water.  For  the  first
hour  the percentages were 0.83, 0.33, and 0.14%, respect-
ively, and for the second hour they were 0.23,  0.11,  and
0.05%.   For  HEX and  nine  other tested  chemicals,  the
authors  found that the volatilization rate from distilled
water  could not be used  to predict the rate  from wetted
soils.  Among the chemicals  tested, there was  no  corre-
lation  between  water  solubility or  vapour pressure and
volatilization  from  soils.  The  volatilization rate for
HEX and its metabolites in soil was primarily dependent on
soil  organic matter content, mainly because of the highly
sorptive characteristics of HEX.

    In a model ecosystem study, Kloskowski et  al.  (1981)
applied 14C-HEX   to 1 kg of humus sand soil (2 mg/kg) and
grew  summer barley by keeping the system under an illumi-
nation of 10 000 lux (12 h light, 12 h dark)  at  20-24 °C
in  an enclosed 10-litre  desiccator with an  aeration  of
10 ml/min.  After 7 days, approximately 19.5% of the orig-
inal  radioactivity was recovered  in the form  of   14CO2
evolved  and 0.5% as  volatilized organics. The  level  of
radiolabelled  compounds  in  the plants  was  13.4 mg/kg,
which  represented a bioaccumulation  factor of 7.1  (i.e.
plant residues divided by soil residues).  It is not clear
whether the plants played a major role in  the  volatiliz-
ation or metabolic fate of HEX, but the total 14C   recov-
ery was over 95%.

    Rieck  (1977c) measured the rate  of volatilization of
HEX  from Maury silt loam soils.  After the application of
100 mg 14C-HEX  to soil, the cumulative evaporation of HEX
and  its  non-polar  metabolites (penta- and  tetrachloro-
cyclopentadiene)  on days 1, 2,  3, 5, 7, and  14 was 9.3,
10.2,  10.6,  10.8,  11.0, and  11.2%,  respectively.  The

results  indicated  that  HEX evaporation  to air occurred
mainly  during  the first  day  after application  and was
probably associated with the surface soil only.

    The  soil sorption properties of compounds such as HEX
can  be  predicted  from their  soil  organic carbon/water
partition  coefficients  (Koc).    Kenaga  (1980) examined
the  sorption  properties  of 100  chemicals and concluded
that  compounds with Koc   values > 1000 are tightly bound
to  soil components and are immobile in soils.  Those with
values < 100 are sorbed less strongly and  are  considered
to  be moderately to highly mobile.  Thus, the theoretical
Koc    value is useful as  an indicator of potential  soil
leachability or binding of the chemical.  The Koc   values
also  indicate whether a chemical is likely to enter water
by leaching or by being sorbed to eroded  soil  particles.
Since  Koc    values  for HEX  are  not  available in  the
literature,   these  values  were  calculated   using  the
following  mathematical  equation,  developed by  Kenaga &
Goring (1980) and Kenaga (1980):

            log Koc = 3.64-0.55 (log WS)

where  WS  is water  solubility  (mg/litre), and  the  95%
confidence  limits  are  ± 1.23 orders  of  magnitude. The
calculated values of Koc for  HEX using the reported water
solubility  values of 2.1 mg/litre (Dal Monte & Yu, 1977),
1.8 mg/litre  (Wolfe et al., 1982), and 0.805 mg/litre (Lu
et  al.,  1975) are  2903,  3159, and  4918, respectively.
Since  these calculated Koc    values are all  > 1000, the
authors  concluded  that  HEX  is  tightly  bound  to soil
components  and  immobile  in the  soil compartment. Simi-
larly, Briggs (1973) concluded that compounds with  a  log
octanol/water partition coefficient (log Pow)   > 3.78 are
immobile in soil.  Log Pow   values for HEX of 5.04 (Wolfe
et  al.,  1982) and  5.51 (Veith et  al., 1979) have  been

    In studies by Chou & Griffin (1983), the  mobility  of
HEX (C-56) in six soils was measured with several leaching
solvents  using  soil thin-layer  chromatography (TLC) and
column leaching studies.  It remained immobile in the soil
when  leached  with  water, landfill  leachate, or caustic
brine,  but was highly  mobile when leached  with  organic
solvents.  A  further  conclusion was  that several degra-
dation  products of HEX migrated through soils faster than
HEX  itself, and that  the degradation products  warranted
further  study.  The sorption  capacity of HEX  was highly
correlated  with the total organic carbon (TOC) content of
soil  materials (r2 = 0.97),  which was  the dominant soil
characterization  parameter.  Sorption appears  to be pre-
dictable  from the TOC content  of soils (Chou &  Griffin,

4.3.  Biotransformation

4.3.1.  Biodegradation

    The  metabolism  of  HEX  by  soil  microorganisms  is
apparently  an  important  process  in  its  environmental
degradation.   Soil degradation is rapid under non-sterile
aerobic  and  anaerobic conditions,  and indirect evidence
for  microbial  involvement  has been  reported  by  Rieck
(1977b,c).   In  one of  his  studies, Rieck  (1977b) used
several types of treatments and soils of different  pH  to
determine  whether the biodegradation of HEX in Maury silt
loam  soil  was  biologically or  chemically  mediated, or
both.  Soils were incubated in glass flasks  covered  with
perforated aluminum foil and kept on a  laboratory  shelf,
presumably  exposed to ambient lighting  through the flask
walls.   When 14C-HEX   was applied to non-sterile soil at
1 mg/kg,  only  6.1%  was recovered  as non-polar material
(either  HEX  or  non-polar degradation  products)  7 days
after  treatment,  and  approximately 71.7%  was polar and
unextractable material. Adjustment of the pH to 4 or 8 had
little effect on these results.  By comparison,  in  auto-
claved soil (the control), 36.1% of the applied  dose  was
recovered  as  non-polar  material  and  only  33.4%   was
recovered as polar and unextractable material.  The degra-
dation   of  HEX  under  anaerobic   (flooded)  conditions
occurred  at  a slightly  faster  rate than  under aerobic
conditions.  However, no sterile, flooded control was used
to determine the effects of hydrolysis, which  could  have
accounted  for the observed effect in this treatment.  The
mean total recovery in all treatments decreased  from  67%
at 7 days to 55% at 56 days.  This decrease was attributed
to volatilization of HEX and/or its degradation products.

    Volatilization  from  soil  was examined  in a further
experiment (Rieck, 1977c).  In a 14-day study, radiocarbon
volatilized  from non-sterile, 14C-HEX-treated    soil was
trapped and assayed. A total of 20.2% of the  applied  14C
was  trapped: 11.2% in  hexane and 9.0%  in  ethanolamine-
water.  Most of the hexane  fraction (9.3% of the  applied
14C)  was  trapped  during the  first  day,  and  probably
represented  volatilized HEX.  However,  the ethanolamine-
water  fraction,  considered  to represent  evolved carbon
dioxide,  was released gradually  over the 14-day  period.
In  the soil analysis,  non-polar (extractable) and  polar
(extractable and unextractable) material accounted for 3.4
and 40.0% of the dose, respectively, during  the  14 days;
total  recovery  was only  63.6% including volatilization.
No metabolic products were identified in the  two  studies
by Rieck (1977b,c).

    Thuma et al. (1978) studied the feasibility  of  using
selected  pure  cultures  (organisms  not  identified)  to
biodegrade  spills of hazardous chemicals,  including HEX,
on  soil.  They tested  23 organisms and found  that  from
2-76% of the applied HEX had been removed from the aqueous

culture  medium within 14 days.  Seven of the 23 organisms
degraded  more than 33% of the HEX within 14 days.  Losses
of HEX by other means than biodegradation  were  accounted
for by using controls.

    Atallah  et  al.  (1980) conducted  an aqueous aerobic
biodegradability  study to determine whether  HEX could be
degraded  to CO2   and at  what rate.  The inoculum  was a
mixed  acclimated  culture containing  secondary municipal
waste  effluent and several strains of  Pseudomonas putida.
14C-labelled HEX was  the  sole source  of carbon  in  the
study,  with the exception  of trace levels  of  vitamins.
Total removal of 14C,   primarily as volatile organic com-
pounds,  was > 80% during the  first day in both  uninocu-
lated  (45 mg  HEX/litre)  and inoculated  (4.5  and 45 mg
HEX/litre) media, although removal was slightly greater in
inoculated media.  14CO2     was released from both media,
indicating  that CO2   was a product of hydrolysis as well
as of biodegradation.  The rate of conversion to CO2   was
initially  higher in the  uninoculated media, but  after 1
week,  became higher in  the inoculated media.  This study
showed  clearly  that HEX  can  be biodegraded  in aquatic
media  under laboratory conditions.  However, Wolfe et al.
(1982)  failed to detect  any difference between  the  HEX
degradation  rates  in  hydrolysis experiments  where non-
sterile natural sediments were added to water (10 g/litre)
and those where sterile sediment was used. They calculated
a  relatively low value (1 x 10-5    ml org-1   h-1;   see
Table 2)  as  a  maximum biodegradation  rate,  and conse-
quently  biodegradation was estimated  to be a  relatively
unimportant fate process in the EXAMS model (see Table 3).

    These  studies indicate that the persistence of HEX in
soil is brief, degradation of more than 90% of applied HEX
to  non-polar  products  occurring within  approximately 7
days.   Factors contributing to this  loss include abiotic
and  biotic  degradation  processes  and   volatilization,
although the relative importance of each is  difficult  to

4.3.2.  Bioconcentration, bioaccumulation, and biomagnification

    Bioaccumulation,  sometimes also expressed as biologi-
cal persistence, is a consequence of the rate  of  elimin-
ation of a compound and the extent of adsorption.

    The  terminology used in this section conforms to that
used by Macek et al. (1979):

*   bioconcentration  implies that tissue  residues result
    only  from  simultaneous  uptake and  elimination from
    exposure  to  the  ambient environment  (e.g., air for
    terrestrial species or water for aquatic species);

*   bioaccumulation  considers all exposures  (air, water,
    and food) of an individual organism to be  the  source
    of tissue residues;

*   biomagnification   defines  the  increase   in  tissue
    residues  observed  at  successively  higher   trophic
    levels of a food web.

Table 3.  Summary of results of computer simulation of the 
fate and transport of hexachlorocyclopentadiene in four 
typical aquatic environmentsa
                        River   Pond    Eutrophic  Oligotrophic
                                        lake       lake
Distribution (%)
  Water column          1.22    14      12.97      2.91b
  Sediment              98.78   86      87.03      97.09

Recovery timec (days)   52      81      58         87

Load reduction (%) by processes:

  Hydrolysis            8.04    17.85   8.29       16.50
  Oxidation             0.00    0.00    0.00       0.00
  Photolysis            18.68   80.39   89.18      82.41

  Biodegradation        0.57    0.23    0.30       0.01

  Volatilization        0.69    1.33    1.56       1.08
   Exportd              72.02   0.20    0.01       0.00
a   Adapted from Wolfe et al. (1982), with correction applied.
b   Value was incorrectly reported as 32.91 in original paper.
c   The time needed to reduce steady-state concentrations by 
    97% (five half-lives).
d   Physical loss from the system by any pathway other than 

    The log octanol/water partition coefficient of HEX has
been experimentally determined to be 5.04 (Wolfe  et  al.,
1982)  and 5.51 (Veith et al., 1979), which would indicate
a  substantial potential for  bioconcentration, bioaccumu-
lation,  and  biomagnification.  Actual  determinations of
bioconcentration  and  bioaccumulation in  several aquatic
organisms,  however, indicate that HEX does not accumulate
to  any great extent  (Lu et al.,  1975; Podowski &  Khan,
1979,  1984; Spehar  et al.,  1979; Veith  et al.,  1979),
mainly because it is metabolized rapidly.

    Podowski  & Khan (1979, 1984) conducted several exper-
iments  on  the  uptake, bioaccumulation,  and elimination
of 14C-HEX   in goldfish ( Carassius auratus) and concluded
that this species rapidly eliminates absorbed HEX.  In one

experiment,  fish were transferred  daily into fresh  sol-
utions of 14C-HEX   for 16 days.  This transfer  of  three
fish/jar  resulted in an  accumulative exposure of  240 µg
of  HEX.  Nominal HEX concentrations  of 10 µg/litre   re-
sulted  in measured water concentrations  (based on radio-
activity)  in the range of  3.4-4.8 µg/litre,   because of
rapid  volatilization  of  the  compound.    Radioactivity
accumulated  rapidly in fish tissue, reaching a maximum on
day 8 corresponding to approximately 6 mg HEX/kg. Since an
undetermined  amount of the  radioactivity was present  as
metabolites,  no  bioconcentration factor  could be calcu-
lated.   From day 8 to  day 16, tissue levels declined  in
spite  of the daily  renewal of exposure  solutions, indi-
cating  that excretion of  HEX and/or its  metabolites was
occurring  more rapidly than uptake.  In a static exposure
to  an initial measured  HEX concentration of  5 µg    per
litre, uptake of the radiolabel by the fish was to a level
corresponding  to 1.6 mg HEX/kg on day 2, accompanied by a
slight  decrease of HEX in  the water. By day  4, approxi-
mately  50% of the radiolabel  had been excreted, and  the
radioactivity  in the water increased.  Over the following
12 days, the radioactivity in both water and fish declined

    Podowski  & Khan (1979, 1984) also studied the elimin-
ation, metabolism, and tissue distribution of HEX injected
intraperitoneally  into goldfish and concluded  that gold-
fish  eliminate  injected  HEX both  rapidly  and linearly
(the  biological half-life was approximately 9 days).  The
fish  (27-45 g) were injected with  39.6 µg 14C-HEX    and
analysed  3 days later.  Of  the 97% of  the radiolabelled
dose  accounted for, approximately 18.9% was eliminated by
the  fish.  Of the  residue found in  the fish, 47.2%  was
extractable  in  organic  solvent (little  of  the  radio-
labelled  material could be identified as HEX, which indi-
cated  that  extensive  biotransformation  had  occurred),
10.6%  consisted  of water-soluble  metabolites, and 20.3%
was  unextractable.  None  of the  metabolites were ident-
ified. The elimination was biphasic, consisting of a rapid
initial phase followed by a slower terminal phase.

    In  another  part  of  these  studies,  the   residual
activity  in several fish tissues was assayed 2, 4, 6, and
8 days  after an injection of 38.4 µg 14C-HEX    per fish.
The activity corresponded to 0.2 and 0.3 µg  HEX/kg in the
spinal  cord and gills, respectively,  concentrations that
remained  constant  throughout  the 8-day  period  of  the
study.   Residues in the kidneys and bile increased within
the  same period from 1-3  and 0-32 µg/kg,   respectively,
indicating elimination by these routes. The authors stated
that  the  increase  probably occurred  from enhanced con-
version  of the parent compound into polar products, which
could  be excreted more easily.  In the other tissues, all
residual levels decreased, leaving only the liver  with  a
level  of more than  1 µg/kg.    The metabolites  were not
identified (Podowski & Khan, 1979, 1984).

    Veith  et  al.  (1979) determined  a  bioconcentration
factor  (BCF)  for  HEX  of  29  in  the  fat-head  minnow
 (Pimephales   promelas).  In a 32-day flow-through study,
30 fish  were exposed to  HEX at a  mean concentration  of
20.9 µg/litre.    Five fish at a time were killed at 2, 4,
8,  16, 24, and 32 days  for residue analysis.  The  study
was  conducted using Lake Superior water at 25 °C (pH 7.5,
dissolved  oxygen  > 5.0 mg/litre,  and  hardness  41.5 mg
CaCO3/litre.   On the basis of its estimated octanol/water
partition  coefficient alone (log Pow = 5.51),   a  BCF of
approximately  9600  would have  been predicted.  However,
HEX  did  not bioconcentrate  substantially, and therefore
deviated  from  the  log P:log BCF  relationship shown for
most of the other 29 chemicals tested by these researchers.

    Lu  et al. (1975) studied  the fate of HEX  in a model
terrestrial-aquatic ecosystem maintained at 26.7 °C with a
12-h  photoperiod.   The  model ecosystem  consisted of 50
sorghum  (Sorghum  vulgare) plants (7.62-10.16 cm tall) in
the  terrestrial portion, while 10 snails  (Physa sp.), 30
water  fleas   (Daphnia   magna), filamentous  green algae
 (Oedogonium   cardiacum),  and  a plankton  culture  were
added  to the aquatic  portion.  The sorghum  plants  were
treated topically with 5.0 mg 14C-HEX  in acetone to simu-
late  a  terrestrial  application of  1.1 kg/hectare.  Ten
early-fifth-instar  caterpillar  larvae  (Estigmene  acrea)
were   placed on the plants.  The insects consumed most of
the  treated plant surface  within 3-4 days.  The  faeces,
leaf  grass,  and  the larvae  themselves contaminated the
moist  sand, permitting distribution of  the radiolabelled
metabolites  by water throughout the  ecosystem.  After 26
days, 300 mosquito larvae  (Culex pipiens quinquefasciatus)
were  added to the ecosystem, and on day 30 three mosquito
fish   (Gambusia  affinis) were added.  The experiment was
terminated  after 33 days, and the various parameters were
analysed.   The  radioactivity  was  then  extracted  with
diethyl  ether from the  water and with  acetone from  the
organisms.   The  results  of  thin-layer  chromatographic
analysis of the extracts are presented in  Table 4.   Data
were  not  reported  for  Daphnia magna  or the  salt marsh
caterpillar.   Uptake in this experiment  occurred through
food  as well as water, and therefore is termed bioaccumu-
lation rather than bioconcentration. Lu et al. (1975) used
the  term ecological magnification  to designate the  bio-
accumulation  factor (BAF).  The BAF  for HEX in fish  was
448  (0.1076 mg/kg fish divided by  0.24 µg/litre   water)
for  the  3-day  exposure period,  indicating  a  moderate
potential  for concentration (Kenaga, 1980).   The BAFs in
algae (< 33-day exposure), snails (< 33-day exposure), and
mosquito  larvae (7-day exposure) were reported to be 341,
1634, and 929, respectively (Lu et al., 1975).

Table 4.  Relative distribution of hexachlorocyclopentadiene (HEX) and 
its degradation products in a model ecosystema
                                     14C-HEX equivalents
                       Water       Algae    Snail    Mosquito   Fish
                       (mg/litre)  (mg/kg)  (mg/kg)  larva      (mg/kg)
HEX                    0.00024     0.0818   0.3922   0.2230     0.1076

Other extractable      0.00204     0.1632   0.3824   0.2542     0.1542

Total extractable14Cb  0.00228     0.2450   0.7746   0.4772     0.2618

Unextractable14C       0.00750     0.0094   0.0814   0.0104     0.0982

Total14Cc              0.00978     0.2544   0.8560   0.4876     0.3600
a   Source: Lu et al. (1975).
b   Sum of HEX and other extractable compounds.
c   Sum of total extractable and unextractable 14C.

    Biomagnification,   measured  as  the  ratio   of  HEX
residues  between  trophic  levels (e.g.,  snail/algae  or
fish/mosquito),  was far less substantial  than bioconcen-
tration. Based on the HEX tissue residues, the snail/algae
ratio  was 0.3922/0.0818 = 4.8 and the fish/mosquito ratio
was 0.1076/0.2230 = 0.48.

    Lu et al. (1975) also studied the metabolism of HEX by
the  organisms  present  in the  model terrestrial-aquatic
ecosystem,  but none of the products was identified except
for HEX. The authors reported that unmetabolized  HEX  re-
presented a large percentage of the total extractable 14C,
being 33% in algae, 50% in snail, 46% in mosquito, and 41%
in  fish.  The percentage of biodegradation was calculated
for each organism (unextractable  14C x 100/total 14C) and
found to be 4% for the algae (in < 33 days), 10%  for  the
snails  (in < 33 days), 2% for the mosquitoes (in 7 days),
and 27% for the fish (in 3 days).  However,  these  values
may underestimate the extent of metabolism, since acetone-
extractable  polar  compounds  were not  considered in the

    The  Velsicol  Chemical  Corporation (1978)  conducted
fish  tissue residue studies in waters located below their
facility in Memphis, Tennessee, USA, and reported that HEX
was  not  detected in  either  catfish or  carp,  although
chlorinated compounds, including octachlorocyclopentadiene
(a  common  co-contaminant),  were detected  in  the  fish
tissue.  This indicated that HEX was not accumulated.  The
possible   source  of  these   other  compounds  was   not
discussed.   In a joint USA federal and state study of the

Mississippi  River at locations  above, around, and  below
Memphis, Bennett (1982) reported that HEX was not detected
in any of the eight fish sample groups analysed by GC/MS.

4.4.  Interactions with other physical and chemical factors

4.4.1.  Phototransformation

    Zepp  et al. (1979) and  Wolfe et al. (1982)  reported
the  results of US EPA  studies on the rate  of HEX photo-
transformation  in  water.   Under a  variety  of sunlight
conditions, in both distilled and natural waters of 1-4 cm
depth,  the  phototransformation  half-life was  < 10 min.
Chou & Griffin (1983) determined a half-life of < 4 min at
740 j/m2.   The addition of natural sediments to distilled
water  containing HEX had little effect on the phototrans-
formation rate.  These findings indicate that the dominant
mechanism  of HEX phototransformation is direct absorption
of  light by the chemical,  rather than photosensitization
reactions   involving   other   dissolved   or   suspended

    The  direct  photoreaction of  HEX  in water  was also
studied  under  controlled  conditions in  the  laboratory
using a monochromatic light (313 nm) with a  mercury  lamp
source  and appropriate filters.  Phototransformation rate
constants,   computed  for  the  study  location  (Athens,
Georgia,  USA, 34 °N latitude), agreed with those observed
in  the sunlight experiments  described above.  Rate  con-
stants  were also computed for  various times of day  at a
latitude  of 40 °N.  The  near-surface phototransformation
rate  constant of HEX at  this latitude on cloudless  days
(averaged over both light and dark periods for 1 year) was
3.9 h-1,    which corresponds to a very rapid half-life of
10.7 min (Zepp et al., 1979; Wolfe et al., 1982).

    These  laboratory researchers suggested that  the pri-
mary  phototransformation product was the hydrated form of
tetrachlorocyclopentadienone  (C5Cl4O,     TCPD), although
it  was  not isolated.   Several chlorinated photoproducts
with  a  higher  relative  molecular  mass  than  HEX were
detected by GC/MS analysis of the reaction mixture. Photo-
lysis  of HEX in methanol gave a product identified as the
dimethyl ketal of TCPD (Wolfe et al., 1982).  According to
Zepp et al. (1979), it is likely that TCPD exists predomi-
nantly  in its hydrated  form in the  aquatic environment.
The  compound  was  not isolated,  supposedly  because  it
rapidly  dimerizes or reacts  to form products  of  higher
relative  molecular mass.  Chou  et al. (1987)  identified
2,3,4,4,5-pentachloro-2-cyclopentenone, hexachloro-2-cyclo-
pentenone,  and hexachloro-3-cyclopentenone as the primary
photodegradation  products, as well as  several other pri-
mary and secondary ones (Chou & Griffin, 1983; Fig. 2).

    Yu & Atallah (1977b) found that, at a concentration of
2.2 mg/litre  in  water, uniformly  labelled 14C-HEX   was
rapidly   converted   to   water-soluble   products   upon
irradiation with light from a mercury vapour  lamp  (light
energy:  40-48%  ultraviolet,  40-43%  visible,  remainder
infrared).   In exposures lasting 0.5-5.0 h, 46-53% of the
radiolabel  was  recovered  in the  form  of water-soluble
products  (compared  with  7% at  initiation), whereas the
amount  recovered by organic (petroleum  ether) extraction
decreased with increasing exposure duration from 25% to 6%
(compared with 66% at initiation).  HEX was  not  detected
among  the photoproducts in the  organic extraction.  Chou
et  al. (1987) also found that dimerization of degradation
products  to form compounds  of higher relative  molecular
mass was only a minor route of degradation.

4.4.2.  Oxidation

    HEX would not be expected to be oxidized  under  ordi-
nary  environmental  conditions.   In the  laboratory, HEX
reacts with molecular oxygen at 95-105 °C to form  a  mix-
ture  of hexachlorocyclopentenones (Molotsky  & Ballweber,
1957).  However, based on  an estimated second-order  oxi-
dation rate constant of 1 x 10-10   M-1   sec-1   at 25 °C
in water (Table 2), the EXAMS computer simulation of Wolfe
et  al. (1982) predicted that HEX would not be oxidized in
the  simulated river, pond, eutrophic lake or oligotrophic
lake (Table 3).

4.5.  Disposal and fate

    HEX  and  HEX-contaminated  material  and  wastes  are
disposed of in secure chemical landfills, by incineration,
and  by deep well injection (US EPA, 1989).  Additionally,
there  are  solid waste  regulations  in the  USA because,
under the Resource Conservation and Recovery Act,  HEX  is
designated  to be a  toxic waste.  German  regulations are
similar  to those of the USA, except that there is no deep
well injection (BUA, 1988).

    Since  the photodegradation products of  HEX have been
identified  only recently and  because HEX has  also  been
found  in areas where waste  has not been disposed  of for
years  (US EPA, 1980c), it  is difficult to determine  its
fate in the environment.


5.1.  Environmental levels

5.1.1.  Air

    Releases  of HEX into  the atmosphere can  result from
the production, processing, and use of HEX,  the  disposal
of  wastes containing HEX,  or from products  contaminated
with HEX (Hunt & Brooks, 1984).  Data sent to the  US  EPA
for 1987 regarding emission levels from companies  in  the
USA indicated that 1400 kg of HEX was emitted into the air
(US  EPA, 1989).  In the  Federal Republic of Germany  and
the Netherlands, about 400-500 kg was emitted to  the  air
in 1987 (BUA, 1988)

    In  September and October 1985,  the Velsicol Chemical
Corporation  determined concentrations of HEX at predeter-
mined   locations  around  its  production  facilities  in
Tennessee, USA.  The study was designed to measure ambient
concentrations  in  the  air during  routine manufacturing
operations. Of the 25 samples collected, 15 were below the
analytical  limit  of detection,  i.e. 0.03 µg  (0.1 ppb).
The air HEX levels in the other samples ranged  between  1
and  10 µg/m3     (0.1-0.9 ppb) when  ambient temperatures
were between 4.4 °C and 27.7 °C (Velsicol Chemical Corpor-
ation, 1986).

    The  highest reported concentration of HEX measured in
homes  in Tennessee was 0.10 µg/m3,    while air levels at
the   Memphis  North  treatment  plant  were  as  high  as
39 µg/m3     (C.S. Clark et al., 1982; Elia et al., 1983).
In an air monitoring study on an abandoned waste  site  in
Michigan,  the average HEX emission rate was 0.26 (± 0.05)
g/h.  In May 1977, HEX  was detected at a  level of 633 µg
per  m3   (56 ppb) in air  samples collected from a  waste
site in Montague, Michigan (US EPA, 1980c).

5.1.2.  Water

    Benoit  & Williams (1981) sampled both untreated water
and drinking-water from a water treatment plant in Ottawa,
Canada. Using solvent extraction analysis with a detection
sensitivity  of 50 ng/litre (or the XAD-2 resin extraction
method  with a detection sensitivity  of approximately 0.5
ng/litre),  the authors  did not  detect any  HEX  in  the
untreated  water, but reported levels  ranging from 57-110
ng/litre  in  the finished  drinking-water.  These results
suggest  that HEX was  introduced into the  drinking-water
during the treatment process. However, the researchers did
not find the source of the HEX.  Meier et al. (1985) found
that HEX can be produced through the chlorination of humic

    Limited monitoring data from production sites revealed
that  HEX was present in  a spot sample at  a level of  18
mg/litre  (February 1977) and a range of 0.156-8.24 mg per
litre (over the month of January 1977) in the aqueous dis-
charge from the Memphis pesticide plant (US  EPA,  1980c).
The  calculated  concentration  of HEX  in the Mississippi
River was 6 µg/litre   (Carter, 1977).  In the  summer  of
1977,  shortly  after  these readings,  a  new waste-water
treatment  plant began operation (Table 5).  Prior to con-
struction of the plant, waste water flowed  directly  into
the  Mississippi River or  through one of  its tributaries
(Elia et al., 1983). Voluntary improvements in controlling
the  discharge from the Memphis plant resulted in reported
levels  of 0.07 µg   HEX/litre  in the Mississippi  River,
near  the mouth of  Wolf Creek (Velsicol  Chemical Corpor-
ation, 1978). HEX has also been identified in the soil and
river sediments downstream from a USA manufacturing plant,
even  after pesticide production was discontinued (US EPA,

5.1.3.  Soil

    Ambient  monitoring data for the  terrestrial environ-
ment  are not available, but  it seems that these  concen-
trations  should be much lower  than those in the  aquatic
environment.   Deposition of HEX from the atmospheric (and
aquatic)  compartments into the terrestrial environment is
expected  to be minimal.  Similarly, direct release of HEX
into the terrestrial environment (i.e. as an  impurity  in
chlorinated  pesticides)  should be  decreasing because of
regulatory  controls on some  products, with the  possible
exceptions  of disposal at waste sites, accidental spills,
and other illegal disposal methods.

Table 5.  Concentrations of selected organic compounds in 
influent waste water at the Memphis North treatment plant, 1978a
                                 Concentration (µg/litre)b
Date               No. of   HEX    HEX-BCHc  HCBCHd  Chlordane
June               1        3      334       57      87
August             5        0.8    329       115     216
September          2        4      292       668     58
October-November   2        0.8    11        17      32
a   From: Elia et al. (1983).
b   Mean values for the number of samples indicated.
c   Hexachlorobicycloheptadiene.
d   Heptachlorobicycloheptene.

5.1.4.  Food

    HEX  was qualitatively detected in  fish samples taken
from  water  near  a  pesticide  manufacturing  plant   in
Michigan (Spehar et al., 1977), but none was  detected  in

fish  samples  taken from  the  waters near  the pesticide
manufacturing  plant in Memphis (Velsicol Chemical Corpor-
ation, 1978; Bennett, 1982).  No information regarding HEX
contamination of other foods is available.

5.2.  General population exposure

    There  are insufficient data to determine the relative
contributions  of  the  various  sources  of  HEX  to  the
environment.   There will be  exposure to HEX  present  in
some  commonly  used  pesticides, and  possibly some flame
retardants,  where HEX is a  contaminant.  The US EPA  has
reported  that exposure of humans  to HEX from the  air or
water  should be  extremely low,  except in  the  case  of
workers  and  residents near  manufacturing, shipping, and
waste  sites,  and  concluded that  general population ex-
posure was not considered to be significant or substantial
(US EPA, 1982).

    The  only other estimates  of relative source  contri-
butions  are from reports completed for the US EPA (Hunt &
Brooks, 1984) and the BUA (1988).  The air  releases  from
manufacturing processes can come from the vents  on  reac-
tors,   process  and  storage   tanks,  and  as   fugitive
emissions.   Hunt & Brooks (1984) estimated that the total
quantity of HEX released from these sources  was  8 tonnes
per  year. In  the Federal  Republic of  Germany  and  the
Netherlands,  HEX emissions were  estimated to be  400-500
kg/year.   HEX can also be  emitted into the air  from the
incineration  and landfilling of HEX-containing waste, the
most accurate estimate being 1 tonne per year.  The  total
annual  estimated release of HEX to the environment in the
USA  is  11.9 tonnes.  These figures  are  only  estimates
because  of  the limited  available  data. They  are given
simply to indicate the relative magnitude of HEX emissions
into the environment.

    Exposure  limit values for various countries are given
in Appendix 1.

5.3.  Occupational exposure

    Occupational exposure can occur both at HEX production
and  processing  facilities  and at  other locations where
HEX-containing waste is present.  For example, the highest
reported workplace air concentrations of HEX were measured
at  the  Louisville, Kentucky,  USA, waste-water treatment
plant,  which received a slug of HEX discharged by a waste
hauler.  Four days after the plant was closed, air concen-
trations  in the primary  treatment area ranged  from 3.05
to  11.0 mg/m3   (270 to  970 ppb) (Morse et  al.,  1979).
During  the clean-up operations air concentrations as high
as  133 mg/m3    (11 800 ppb)  were reported  (Kominsky  &
Wisseman, 1978).

    In  1982, the Velsicol  Chemical Corporation used  the
Southern  Research Institute (SRI) sampling  method at the
Memphis  (Tennessee) and Marshall (Illinois) facilities to
evaluate  possible exposure of  workers to HEX  vapour and
the effectiveness of engineering controls.  Tables 6 and 7
show the HEX concentrations measured at various points.

    At  the Memphis facility almost one-half of the worker
8-h  time-weighted  average  (TWA) air  HEX concentrations
were  at or above  the USA Threshold  Limit Value of  0.11
mg/m3   (0.01 ppm) (OSHA, 1989). At the Marshall plant all
six TWA values were above 0.11 mg/m3.   It should be noted
that  in Tables 6 and 7 the results of employee monitoring
are reported without regard to respirator use. Respirators
are  required to  be worn  in operations  in these  plants
where HEX exposure is possible.

    Information  on guidelines, recommendations, and stan-
dards  used in various  countries is given  in  Appendix 1
(Table 21).
Table 6.  Summary of hexachlorocyclopentadiene monitoring, Memphis, Tennessee, USAa
Unit           Description                No. of    Average    Range of sample   Average 
                                          samples   duration   concentrationsb   TWAb
                                                    (min)      (ppm)             (ppm)  
HEX            Process operator           2         445        0.009-0.011       0.009
HEX            No. 1 operator             5         432        0.006-0.033       0.015
HEX            No. 2 process operator     5         418        0.006-0.029       0.014
HEX            No. 2 cyclo operator       5         417        0.001-0.048       0.017
HEX            No. 2 chlorine operator    6         415        0.004-0.0161      0.035
               a) HEX Bottoms drumming    1         50         0.016
HEX            Area sample control room   12        476        0.002-0.018       0.009
HEX            Brinks filter cleaning     2         387        0.004-0.006       0.005

Formulations   HEX drummers               4         407        0.002-2.0337      0.010

Material       HEX railroad tank car      1         279        0.013             0.008
 handling      unloading

Endrin         R2 filter operator         1         281        0.003
Endrin         R1 operator                1         334        0.002

Chlorendic     No. 1 operator             2         437        0.0077-0.0102     0.008

Chlorendic     No. 2 operator D34         2         440        0.0107-0.0198     0.014

Chlorendic     No. 2 operator R6          2         437        0.0065-0.0169     0.011

Chlorendic     Packaging operator         1         396        0.035             0.031

Table 6 (contd.)
Unit           Description                No. of    Average    Range of sample   Average 
                                          samples   duration   concentrationsb   TWAb
                                                    (min)      (ppm)             (ppm)  
Chlorendic     Area sample - control      3         475        0.0003-0.0014     0.001
 anhydride     room

Heptachlor     No. 1 operator             2         407        0.007-0.009       0.007

Heptachlor     No. 2 operator             2         415        0.006-0.009       0.007

Heptachlor     237 operator               2         392        0.006-0.019       0.011

Heptachlor     Utility operator           1         363        0.006             0.005

Heptachlor     Cleaning sparkler filter   3         44         0.002-0.005       0.0003
               a) ceiling sample          1         15         0.006
a   From: Levin (1982a).
b   ppm = parts of HEX per million parts of air by volume.
    TWA = 8-h time-weighted average. The TWA calculation was made assuming
          that the only chemical exposure occurred during the sampling period.

Table 7.  Summary of hexachlorocyclopentadiene monitoring, Marshall, Illinois, USAa
Unit         Description                 No. of   Average    Range of sample   Average 
                                         samples  duration   concentrations    TWAb
                                                  (min)      (ppm)             (ppm)
Chlordane    No. 1 operator              8        451        0.0091-0.0316     0.017
Chlordane    No. 2 operator              8        455        0.008 -0.0195     0.013
Chlordane    No. 3 operator              8        451        0.0002-0.0325     0.014
Chlordane    Area sample -               13       433        0.0002-0.0254     0.016
             North control room
Chlordane    Area sample -               10       435        0.001-0.0276      0.015
             South control room
Chlordane    HEX filter changing         1        15         0.1322
Chlordane    Waste handling HEX          6        307        0.0006-0.0606     0.020
             a) HEX mud drumming -       2        15         0.0005-0.0061
                ceiling sample
             b) Loading HEX waste        2        15         0.1199-0.2325
                truck - ceiling sample
             c) Sump pit dumping -       2        15         0.0333-0.1129
                ceiling sample
a   From: Levin (1982a).
b   ppm = parts of HEX per million parts of air by volume.
    TWA = 8-h time-weighted average. The TWA calculation was made assuming that the 
          only chemical exposure was during the sampling period.

6.1.  Absorption, retention, distribution, metabolism,
elimination, and excretion

6.1.1.  Oral

    In  a study by  Mehendale (1977), male  Sprague-Dawley
rats  (225-250 g body  weight) were  administered   5 µmol
of  14C-HEX   (approximately 5.5 mg/kg) by oral intubation
as 0.2 ml of a solution in corn oil. The total  14C    ac-
tivity contained in the dose was approximately 1 µCi.  The
animals  were maintained in metabolism cages and the urine
and  faeces were collected.  About 35% of the administered
dose was collected in the urine and only 10% was collected
in the faeces.  More than 87% of the 14C   activity in the
urine  and  more than  60% of the  activity in the  faeces
appeared  during  the  first  day.  Only  a  small  amount
(approximately  0.5%)  of the original  dose was recovered
in  the kidneys and liver.  The author speculated that, in
view of the low total recovery of the administered dose, a
major part of the dose (> 50%) had been  excreted  through
the lung. This speculation was later proven to  be  unwar-
ranted  because  subsequent  studies (Dorough,  1979),  in
which  exhaled air and lung and tracheal tissues were ana-
lysed, showed that this was not the case.  There is strong
evidence to suggest that, after oral dosing with  HEX,  at
least  part of the  faecal contents contained  a  volatile
constituent that could be readily lost if the samples were
dried  and powdered, as they were in this case. An extrac-
tion  procedure, using the major tissues and excreta, fol-
lowed  by thin-layer chromatography, showed  that at least
four  water-soluble (polar) metabolites were produced, but
not identified, after oral dosing.

    In a study designed to re-examine some of the findings
and  observations  of  Mehendale  (1977),  Dorough  (1979)
investigated the accumulation, distribution, and excretion
of  14C-HEX   after its  administration to rats  and  mice
either  as a single oral  dose or as a  component of their
diet. The principal results of this study were reported by
Dorough  & Ranieri (1984).  The animals used were male and
female Sprague-Dawley rats, weighing between 200 and 250 g
body  weight,  and  male and  female Sprague-Dawley albino
mice,  weighing between 25 and 30 g.  Two female rats were
dosed,  by gavage, with HEX  (20 mg/kg) in 0.9 ml of  corn
oil  and  were  immediately placed  in separate metabolism
cages  through  which air  was  drawn at  600 ml/min.  The
evacuated  air  was  passed through  two  high  efficiency
traps.   Since less than 1%  of the administered dose  was
recovered from the traps, it was considered to be conclus-
ive  evidence that  the pulmonary  route is  not of  major
importance in the excretion of HEX (Dorough, 1979).

    Dorough (1979) conducted single dose studies by admin-
istering, with a dosing needle, either 2.5 or  25 mg  14C-
HEX/kg  body weight (dissolved in  0.9 ml of corn oil  for
rats  and in 0.2-0.3 ml for mice). The animals were killed
at  1, 3, or 7 days  after dosing, and samples  of muscle,
brain, liver, kidneys, fat, and either ovaries  or  testes
were removed and analysed for 14C   activity.   Urine  and
faeces  were  also  collected during  the  period  between
dosing  and tissue sample collection.  No appreciable dif-
ferences due to sex or species were found in the excretion
patterns.   The  liver, kidneys,  and  fat were  the  most
important deposition sites for 14C   residues in both rats
and  mice, the levels  in the kidneys  of rats and  in the
liver of mice being the highest.

    In  the same study (Dorough, 1979), rats and mice were
also  placed on diets  containing 1, 5,  or 25 mg  14C-HEX
per  kg. Assuming a daily food intake of 15 g for rats and
5 g for mice, this would give daily dose rates  of  0.066,
0.330, and 1.666 mg/kg for rats and 0.182, 0.910, and 4.55
mg/kg  for mice.  Feed was  replaced in the feeders  every
12 h  to minimize the  loss of 14C-HEX    (from volatiliz-
ation), and the feeding study was carried out for 30 days.
During  this period, rats and mice were killed at 1, 3, 7,
12,  15,  or 30 days.   The  surviving animals  were  then
returned  to a normal diet  for up to 30 days  and, during
this post-treatment period, animals were killed at  1,  3,
7,  15, or  30 days after  the last  exposure.  The  total
excretion (urine and faeces) of the radiolabel ranged from
63-79%  of the consumed 14C-HEX,   which was significantly
lower than that found in the single-dose  study  (73-96%).
In  all cases, the liver,  kidneys, and fat contained  the
highest  amounts of 14C,   and  it appeared that a  steady
state  for these levels was  reached after 15 days  of the
feeding  phase.  A good  correlation was observed  between
the level of HEX in the diet and the 14C-levels   found in
all the examined tissues.  In a separate  experiment  with
male  rats, in which  the bile duct  was cannulated and  a
single  dose  of  14C-HEX    (25 mg/kg)  was  administered
orally, only 16% of the dose was excreted in the bile. The
extraction characteristics of the radiocarbon compounds in
the excreta showed that they were primarily  polar  metab-
olites, some of which were capable of being  converted  to
organic-soluble compounds after acid-catalysed hydrolysis.

    In   a  comparative  study  of   the  pharmacokinetics
of 14C-HEX    after  intravenous  and oral  dosing,  Yu  &
Atallah  (1981) dosed Sprague-Dawley rats  (240-350 g body
weight) with either 3 or 6 mg 14C-HEX  (specific activity:
0.267 mCi/mmol).  The doses ranged from 8.5 to 25.6 mg/kg.
Shortly  after oral dosing, 14C   activity appeared in the
blood and reached a maximum after approximately 4 h.

    The  14C   activity appeared  in most of  the  tissues
analysed  at 8, 24,  48, 72, 96,  and 120 h after  dosing.
Following oral dosing, there were higher residue levels in
the kidneys and liver than in any other  tissue,  although
these levels were generally much lower than those observed
after  intravenous  dosing.   For example,  at  24 h after
dosing, the kidneys and liver were found to  contain  only
0.96  and  0.75%,  respectively, of  the administered oral
dose, while these organs retained 2.92 and 4.68%, respect-
ively,  of  the  administered intravenous  dose.  A higher
proportion (15.07%) of the 14C   activity was found in the
digestive system (duodenum and large and small intestines)
after  oral dosing.  Coupled  with the increased  rate and
extent  of  faecal  excretion  after  oral  administration
(approximately  72%),  compared to  that after intravenous
dosing (approximately 20%), this would suggest that only a
fraction  of  the  orally administered  dose was absorbed.
About 17% of the oral dose was excreted in the urine.

    Both   urinary  and  faecal  metabolites   were  again
characterized  as polar because  of their insolubility  in
organic solvents.  Unchanged HEX was not detected  in  any
of the samples examined. Only 11% of the 14C   content was
soluble  in organic solvents  and a further  32% was  con-
verhydrolysis. This indicated,  perhaps, the  formation of
metabolic ester conjugates.

    Lawrence  & Dorough (1982) made a comparative study of
the  uptake,  disposition,  and elimination  of  HEX after
administering  radiolabelled 14C-HEX   by  the intravenous
(10 µg/kg),  inhalation (24 µg/kg),  and oral routes (6 mg
per  kg) to Sprague-Dawley  rats weighing between  175 and
250 g,  respectively. They noted  that while doses  in the
microgram range were useful for monitoring the urinary and
faecal  excretion of HEX, much higher doses (about 6 mg/kg
in  0.5 ml of  corn oil,  and with  a 4-fold  increase  in
radiocarbon  activity) were necessary to  obtain levels in
the  principal organs that could be measured with any pre-
cision.  Indeed, the doses  administered orally were  some
250  and  600 times  the inhaled  and  intravenous  doses,
respectively.   In agreement with other researchers, these
authors  attributed the lack  of measurable levels  in the
organs,  following the administration of low doses, to the
poor  bioavailability of HEX when given by the oral route.
The total radiolabel recovery immediately after the admin-
istration of the dose was 98.0 ± 5.3% (mean ± S.D.).  Rats
dosed  orally eliminated 2-3 times more of the dose in the
faeces than those dosed by the intravenous  or  inhalation
route.  A maximum blood level was reached at approximately
2 h after dosing.  The peak was broad with  similar  blood
concentrations  between 2 and 5 h, perhaps indicating that
absorption  occurred along the gastrointestinal tract over
this  period  in  a quasi-steady  state  with elimination.
Biliary  excretion  was  again confirmed  as being greater
after  oral  dosing  than after  intravenous or inhalation

dosing,  but it still only accounted for 18% of the admin-
istered   dose.  This  observation  agreed  with  previous
studies  and, more importantly,  with the report  of Yu  &
Atallah (1981), who administered comparable dose levels by
the oral route.  Lawrence & Dorough (1982)  also  reported
that  the faecal material contained predominantly polar or
unextractable  material, as did  the bile.  These  authors
considered that this was a clear indication  that  14C-HEX
was extensively metabolized to polar products by  the  gut
contents,  since only approximately  50% of 14C-HEX    was
recovered when it was added to rat stomach  contents  that
were then immediately extracted with hexane.

    A  more recent comparative  study (El Dareer  et  al.,
1983) essentially confirmed the findings of Yu  &  Atallah
(1981)  and  Lawrence  & Dorough  (1982). Male Fischer-344
rats  with an average body  weight of 169 g were  dosed at
a level of 4.1 and 61 mg/kg with approximately 1 ml  of  a
solution  of  14C-HEX   dissolved  in  a 1:1:4  mixture of
Emulphor  EL620, ethanol, and water.  Little radioactivity
appeared as exhaled 14CO2.

6.1.2.  Inhalation

    In  studies by Dorough  (1980) and Lawrence  & Dorough
(1981, 1982), rats were exposed to 14C-HEX   vapour  in  a
specially designed, single animal inhalation exposure sys-
tem.  Each animal was exposed  to the vapours in  a rodent
respirator, with the exhaust vapours from the system pass-
ing through a filter pad made from  expanded  polyurethane
foam.  The flow rate and concentration of HEX was measured
prior to and after passing through the respirator contain-
ing the exposed animal. The difference between the amounts
of  HEX in the  input and output  was assumed to  be equi-
valent  to the  retained dose.  Rats were  exposed  for  a
period  of 1 h and received doses in air which ranged from
1.4  to 37.4 mg/kg body weight (Lawrence & Dorough, 1981).
Immediately  after the 1-h  exposure, the recovery  of the
dose retained by the animal was 91.8 ± 8.5% (mean ± S.D.).
Exposed  animals  were  immediately placed  in  metabolism
cages  for  72 h, during  which  time faeces,  urine,  and
expired  air were collected.  The animals were then killed
and  certain of their tissues analysed for 14C   activity.
Less  than  1% of  the  retained radiocarbon  was  expired
during the 24-h period immediately following exposure, and
no  radiocarbon was detected as 14CO2.      Only about 69%
of  the inhaled dose was  recovered, which was much  lower
than that recovered after intravenous (85%) or oral dosing
(82%).  Since recovery of the dose immediately  after  the
administration  of  the inhalation  dose was approximately
92%,  the  reduced  recovery during  the  72-h post-dosing
period led to the speculation that a  volatile  metabolite
was formed during this period, but attempts to collect and
identify this metabolite were not successful.

    No kinetic parameters were reported in either  of  the
publications  by Lawrence & Dorough (1981, 1982), although
blood  concentration-time data during the 1-h exposure and
the  following 6 h were presented.  Elimination during the
subsequent 6 h appeared to relate to a  complex  pharmaco-
kinetic  model  with a  terminal  rate comparable  to that
reported  for the intravenous  route, the half-life  being
approximately 30 h.

    The elimination via the bile was relatively  low  (8%)
after  inhalation exposure, compared with 13 and 18% after
intravenous  or  oral  administration  of  the  same  dose
(5 µg/kg)    (Lawrence & Dorough,  1982). The fraction  of
the  dose recovered in the  faeces and urine (23  and 33%,
respectively) was about the same as that  recovered  after
the  intravenous dose, except  that more was  recovered in
the   urine  than  in  the  faeces  after  the  inhalation
exposure,  while the reverse was observed after the intra-
venous dose.

    A  comparative study of the  uptake, distribution, and
elimination of 14C-HEX  (El Dareer et al., 1983) confirmed
and extended the conclusions reached by Lawrence & Dorough
(1981,  1982)  concerning  pulmonary exposure.  Individual
Fischer-344 rats weighing between 125 and 190 g  (with  an
average weight of 169 g) were placed in  metabolism  cages
and  exposed by inhalation.  The dose received by each rat
over a 2-h exposure period was calculated from  the  total
amount   of  radioactivity  recovered  from  the  tissues,
faeces,  urine, and exhaled air.   The animal fur was  not
included.   The dose received  by the exposed  animals was
between  1.3 and 1.8 mg/kg  body weight. The  animals were
killed  at either 6 or  24 h after they were  removed from
the  inhalation  exposure.   Whole blood,  plasma,  liver,
kidneys,  voluntary  muscle (gastrocnemius),  subcutaneous
fat,  brain, skin (ears), and the residual carcass (except
for the skin and fur which were discarded)  were  analysed
for 14C   activity, as were the urine, faeces, and exhaled
air.  The principal sites  of deposition were  the  lungs,
kidneys,  and liver. Only  approximately 1% of  the radio-
label was identified as 14CO2.     No intact HEX was found
in  any of  the tissues;  the majority  of the  radiolabel
extracted  was polar (water soluble).  These findings were
similar to those of Lawrence & Dorough (1981, 1982).

6.1.3.  Dermal

    No  studies on the pharmacokinetics or distribution of
dermally  applied HEX were found  in a survey of  the pub-
lished  literature.   Although  no qualitative  studies or
estimates  of the uptake of  HEX through skin were  found,
studies have been reported in which discoloration  of  the
skin  was  observed after  the  dermal application  of HEX
(Treon at al., 1955; IRDC, 1972).  In these reports, toxic

response,  leading  to  death,  was  observed  in  several
instances,  which  would  suggest that  HEX  was  absorbed
transdermally into the systemic circulation.

6.1.4.  Comparative studies

    Each  of the four major  studies (Yu & Atallah,  1981;
Lawrence & Dorough, 1981, 1982; El Dareer et al., 1983) of
the  uptake and distribution of HEX involved more than one
route of uptake.  One objective of each of  these  studies
was to compare the exposure routes.  The observations made
were as follows:

*   The principal routes of excretion were via  the  urine
    and faeces. Considerably more of the administered dose
    was  excreted in the faeces  after oral administration
    than  after  dosing  by the  intravenous or inhalation
    route,  probably  as  a consequence  of  the increased
    biliary  excretion after oral dosing  and the interac-
    tion  or metabolism of the dose by gut and faecal con-
    tents.   More of the administered dose was excreted in
    the   urine  than  in  the   faeces  after  inhalation
    exposure,  while the reverse was the case after intra-
    venous administration.

*   Biliary  excretion  occurred  after administration  by
    each of the three routes. For similar doses, the frac-
    tion of the dose eliminated by this route was  in  the
    order oral > intravenous > inhalation.

*   Comparative  distribution to the major organs and tis-
    sues  is presented in Tables 8, 9, and 10. The princi-
    pal  organs to which HEX  was distributed by the  sys-
    temic  circulation  were  the kidneys  and liver.  The
    lungs and trachea contained the highest concentrations
    of HEX after inhalation exposure.

*   There was a significantly higher retention of 14C   in
    the  carcass, at 72 h post-dosing, after dosing by the
    inhalation  and  intravenous  routes than  after  oral
    dosing (Table 10).

6.1.5.   In vitro studies

    Yu  & Atallah (1981)  examined the ability  of  liver,
faecal,  and gut homogenates  to metabolize HEX  in  vitro.
In   an  apparent  first-order kinetic  process,  HEX  was
metabolized  by gut content, faecal, and liver homogenates
with  half-lives of 10.6,  1.6, and 14.2 h,  respectively.
When  mercuric chloride (HgCl2)   was added to the gut and
faecal  homogenates as a bacteriocide, the half-lives were
increased to 17.2 and 6.2 h, respectively, indicating that
the  gut and faecal flora contributed significantly to the
metabolism  of HEX.  Denaturation of  the liver homogenate
had virtually no effect on the  in  vitro  metabolic  rate
indicating,  perhaps, that there was only limited involve-
ment of liver microsomes or other enzyme-dependent process.

Table 8.  Distribution of radioactivity (expressed as percentage of administered 
dose) from 14C-HEX in rats dosed by various routesa
                       Oral dose           Intravenous         Inhalation dose   
                 Low doseb    High doseb   doseb         Group Ac     Group Bb   
                 (4.1 mg/kg)  (61 mg/kg)   0.59 mg/kg    (1.0 mg/kg)  (1.4 mg/kg)
Faeces           74.5 ± 2.8   65.3 ± 6.9   34.0 ± 1.0d   28.7 ± 4.3   47.5 ± 6.4 
Urine            35.5 ± 2.5   28.7 ± 4.2   15.8 ± 1.4    41.0 ± 4.8   40.0 ± 6.6 
Tissues          2.4 ± 0.6    2.4 ± 0.1    39.0 ± 1.0    28.9 ± 1.6   11.5 ± 0.8 
CO2              0.8 ± 0.0    0.6 ± 0.0    0.1 ± 0.0     1.4 ± 0.3    1.0 ± 0.5  
Other volatile   0.2 ± 0.0    0.3 ± 0.0    0.1 ± 0.0                             
Total recovery   118 ± 3.0e   97 ± 7.0     89 ± 2.0      100          100        
a   Adapted from: El Dareer et al. (1983). Values represent the mean percentage
    of dose ± S.D. for three rats.
b   At 72 h after dosing or exposure.
c   At 6 h after exposure.
d   Plus intestinal contents.
e   For an unexplained reason, the total recovery for this dose was higher than 
    theoretical.  If the percent recoveries for this dose are "normalized" to 
    100%, differences in distribution for the two doses are minimal, indicating 
    that no saturable process is operative in this dose range.
Table 9.  Fate of radiocarbon (expressed as percentage of 
administered dose) after oral, inhalation, and intravenous 
exposure of rats to 14C-HEXa
                           Cumulative percent of dose
                    Oralb          Intravenousc   Inhalationd
  Urine             22.2 ± 1.8     18.3 ± 5.2     29.7 ± 4.5
  Faeces            62.2 ± 8.0     21.1 ± 7.1     17.0 ± 7.5
  Urine             24.0 ± 1.9     20.7 ± 5.6     32.5 ± 5.1
  Faeces            67.7 ± 5.1     30.4 ± 1.7     21.0 ± 7.5
  Urine             24.4 ± 1.9     22.1 ± 5.7     33.1 ± 4.5
  Faeces            68.2 ± 5.1     47.4 ± 1.9     23.1 ± 5.7
  Body              0.2 ± 0.2      15.7 ± 7.8     12.9 ± 4.7
  Total Recovery    92.8 ± 4.7     85.2 ± 4.8     69.1 ± 9.6
a   Adapted from: Dorough (1980) and Lawrence & Dorough (1982).
b   Dose (7 µg/kg body weight) administered in 0.5 ml corn oil.
c   Dose (5 µg/kg body weight) administered in 0.2 ml 
    saline:propylene glycol:ethanol (10:4:1) by injection into 
    the femoral vein.
d   Doses administered as vapours over a 1-h exposure period 
    to achieve doses of about 24 µg/kg body weight.

    El Dareer et al. (1983) incubated 14C-HEX   with homo-
genates of liver, faeces, and intestinal (large and small)
contents, as well as with whole blood and plasma.  Samples
were taken at 0, 5, and 60 min.  The results, presented in
Table 11,  clearly demonstrated the chemical reactivity of
HEX  and  its ability  to  bind components  of  biological

Table 10.  Distribution of HEX equivalentsa in tissues and 
excreta of rats 72 h after oral, inhalation, and intravenous 
exposure to 14C-HEXb,c
Sample               Oral dose    Inhaled dose   Intravenous dose
                     (6 mg/kg)d   (24 µg/kg)     (10 µg/kg)
 ng/g of tissue
 Trachea             292 ± 170    107.0 ± 65.0   3.3 ± 1.7
 Lungs               420 ± 250    71.5 ± 55.2    14.9 ± 1.1
 Liver               539 ± 72     3.6 ± 1.9      9.6 ± 1.1
 Kidneys             3272 ± 84    29.5 ± 20.2    22.3 ± 0.6
 Fat                 311 ± 12     2.8 ± 0.4      2.3 ± 0.2
 Remaining carcass   63 ± 40      1.3 ± 0.6      0.5 ± 0.1

 percentage of dose
 Whole body          2.8 ± 1.1    12.9 ± 4.7     31.0 ± 7.8
 Urine               15.3 ± 3.3   33.1 ± 4.5     22.1 ± 5.7
 Faeces              63.6 ± 8.5   23.1 ± 5.7     31.4 ± 1.9
 Total recovery      81.7 ± 6.7   69.1 ± 9.6     84.6 ± 4.6
a   One HEX equivalent is defined as the amount of radiolabel 
    equivalent to 1 ng of HEX, based on the specific activity of 
    the dosing solution.
b   Adapted from: Dorough (1980) and Lawrence & Dorough (1982).
c   All values are the mean ± S.D. of three replicates.
d   It should be noted that the oral dose was 250 and 600 times 
    that of the inhaled and intravenous doses, respectively.  
    This was necessary because residues were not detected in 
    individual tissues of animals treated orally at doses of 
    5-25 µg/kg.

6.2.  Metabolic transformation

    No  primary metabolites or conjugates of HEX have been
identified.  The data available on the pharmacokinetics of
HEX  after  dosing by  the  oral, inhalation,  and  dermal
routes  are presented in sections 6.1.1, 6.1.2, and 6.1.3.
In  studies  by  Dorough  (1980)  and  Lawrence  & Dorough
(1982), the principal routes of excretion were shown to be
via  the urine and faeces.  No unchanged HEX was  found in
either,  indicating  that  HEX was  involved  in extensive

    In studies with rats and mice fed a diet containing 1,
5, or 25 mg 14C-HEX/kg,   63-79% of the consumed  HEX  was
recovered  in the urine and faeces (Dorough, 1979; Dorough
&  Ranieri, 1984).  The extraction  characteristics of the
radiocarbon compounds in the excreta showed that they were
primarily  polar  metabolites,  some of  which were trans-
formed  to organic-soluble compounds  after acid-catalysed

Table 11.  Extractability of 14C-HEX and radioactivity derived from 
saline and various biological preparationsa
Preparation   Time      First Extraction     Second Extraction  Pellet
              (min)   Organicb     Aqueous   Organic  Aqueous
Saline        0       99.6 (92.4)  0.4
              5       99.1 (92.8)  0.9
              60      98.8 (94.6)  1.2

Liver         0       55.0 (74.4)  8.0       24.5     1.0       11.6
              5       42.8 (49.7)  15.2      15.0     4.7       22.2
              60      11.1         18.8      5.9      2.4       51.8

Plasma        0       22.2 (61.7)  7.2       50.2     0.8       19.6
              5       19.7 (66.3)  25.0      33.6     2.0       19.6
              60      1.4          43.4      21.      3.9       30.2

Whole blood   0       16.2 (60.4)  3.8       27.9     1.2       50.8
              5       2.8          21.6      13.4     1.6       60.6
              60      0.6          27.4      12.0     1.4       58.6

Faeces        0       90.0 (93.7)  0.6       8.0      0.2       1.2
              5       83.4 (87.8)  0.8       9.0      0.6       6.2
              60      40.5 (61.0)  2.8       31.3     3.0       22.4

Intestinal    0       93.7 (94.7)  0.6       4.6      0.2       1.0
 contents     5       82.8 (89.5)  1.6       8.6      1.0       5.9
              60      66.3 (87.0)  4.6       15.4     2.4       11.3
a   From: El Dareer et al. (1983). Values represent the percentage of 
    the total radioactivity in the respective fraction.
b   Values in parentheses represent the percentage of the 
    radioactivity in the fraction as HEX.

    In  a comparative study of the pharmacokinetics of HEX
after intravenous or oral dosing at 8.5-25.6 mg/kg  (Yu  &
Atallah,  1981), urinary and faecal metabolites were again
characterized as polar because of their poor solubility in
organic solvents.  No unchanged HEX was found.   Only  11%
of the 14C   content of the excreta was soluble in organic
solvents, and a further 32% of the extract  was  converted
to  organic-soluble compounds after  acid-catalysed hydro-
lysis.  This  indicated,  perhaps, that  metabolite  ester
conjugates had been formed.

    Yu & Atallah (1981) also performed  in vitro  metabolic
studies  in which they  incubated HEX with  liver, faecal,
and gut-content homogenates (see section 6.1.5).

    After  Lawrence & Dorough (1982) had dosed rats by the
oral,  inhalation,  and  intravenous  routes   with   14C-
labelled HEX at 6 mg/kg, 24 µg/kg  and 10 µg/kg,  respect-
ively, they found that the faecal and bile  contents  con-
tained  mostly polar metabolites.  These authors suggested
that  HEX was rapidly metabolized to polar products, since
only  about 50% of the HEX was recovered when it was added
to rat gut contents and immediately extracted with   n-hex-
ane.   In addition, the  authors noted that  approximately
15.8 ± 4%  of the radiolabel  that appeared in  the faeces
within 24 h after dosing was volatile, indicating  that  a
catabolite was probably produced.

    El Dareer et al. (1983) dosed rats by  the  inhalation
route  so that individual animals received between 1.3 and
1.8 mg/kg  body weight over  a 2-h exposure  period.  They
were killed 6 or 24 h after removal from exposure.  No in-
tact HEX was found in any of the tissues, and the majority
of  the extractable material was polar (water soluble), in
accordance  with the findings of Lawrence & Dorough (1981,
1982).   As a part  of this same  study, El Dareer  et al.
(1983)  incubated  14C-HEX    with homogenates  of  liver,
faeces, and intestinal (large and small) contents, as well
as  with whole blood  and plasma.  These  in  vitro studies
were designed to assess the reactivity and binding charac-
teristics  of  HEX.   The results,  presented  in Table 8,
clearly show chemical lability of HEX and its  ability  to
bind  the components of  biological material (see  section

    Despite  these efforts to characterize HEX metabolism,
no metabolites were identified.  This observation suggests
that an attempt to rectify this deficiency would be a high

6.3.  Reaction with body components

    The  toxic mechanisms of hexachlorocyclopentadiene are
not  well understood.  HEX  has been shown  to react  with
olefins  and other organic molecules such as aromatic com-
pounds.  Using the available  data, especially those  from
studies comparing the various routes of exposure,  a  very
general  and  hypothetical  rationale can  be developed to
suggest possible reactions with body tissue.

    The  reactivity  of HEX  shows  a high  potential  for
transformation  and reaction with other chemicals. Absorp-
tion  from  the  gastrointestinal contents  is  relatively
inefficient, probably due to the interaction of  HEX  with
the gastrointestinal contents and metabolism by intestinal
flora.  The fact that HEX did not appear to be interactive

with the gastrointestinal epithelia in the kinetic studies
discussed in this chapter was probably due to its dilution
in the carrier vehicle, as well as its  interaction  with,
and metabolism by, the gut contents.  However,  in  short-
term repeated oral dosing studies (SRI, 1981a,b), at doses
of  19 mg/kg  or  more, inflammation  and  hyperplasia was
noted in the forestomach (see Table 16).  In addition, the
interaction  of HEX after dermal  contact was marked by  a
distinct discoloration of the skin. This suggests a  "site
of uptake"  interaction, probably similar to that observed
in the lungs after pulmonary uptake.

    During inhalation and the passage of HEX  through  the
lung  tissue to reach the systemic circulation, metabolism
to  water-soluble  compounds  probably occurs  and  HEX is
eliminated  through the kidneys.  However,  an intravenous
dose  may be bound  unchanged to blood  components  (e.g.,
haemoglobin) and remain attached until reaching the liver.
The relatively slow elimination of the radiolabel from the
systemic circulation  after intravenous  dosing with  14C-
HEX  (approximate terminal half-life of  30 h)  suggests a
bioaccumulation  potential,  at  least  for  some  of  the
metabolites,  since little HEX  appears to remain  in  the

    Rand  et al. (1982b) showed that the cellular level in
lung  tissue underwent significant changes after HEX inha-
lation.  HEX vapour, administered by the inhalation route,
in  addition  to binding  to  epithelial lung  tissue, was
found  to bind to  the extracellular lining  in the  lung.
Binding  to  bronchiolar  Clara  cells,  which  contribute
important  materials  to  the extracellular  lining of the
peripheral airways, was observed after inhalation exposure
in  rats and monkeys (Rand  et al., 1982a).  HEX  was also
found, in  in vitro studies, to bind to the  components  of
whole  blood, plasma, liver, and faecal homogenates and to
gastrointestinal contents (El Dareer et al., 1983).  Thus,
irrespective of the route of administration, the principal
sites  of toxic action  seem to be  the lungs, liver,  and
kidneys. This observation is supported by the results from
the toxicity testing reported in chapter 8.


7.1.  Microorganisms

    The  effects  of  HEX  on  microorganisms  have   been
studied  in aqueous and soil systems.  Many of the aqueous
concentrations  used  in  these experiments  exceeded  the
upper  limit  of  aqueous  solubility  (0.8-2.1 mg/litre).
These  concentrations  were  usually obtained  by using an
organic  solvent vehicle to disperse the chemical in aque-
ous  media.  The environmental significance of the results
should be interpreted with this aspect in mind.

    Cole  (1953) inoculated 10 strains of common human and
animal  pathogens into growth media that contained various
concentrations  of HEX.  The inhibiting  concentration, or
lowest concentration in which no growth was observed after
96 h  of  contact,  ranged from  1-10 mg  HEX/litre.   The
Addition of 5 or 10 mg HEX/litre to sewage effluent inocu-
lated  with  Salmonella typhosa was found to be more effec-
tive  than similar concentrations of  chlorine in reducing
counts of total bacteria, coliforms, and  S. typhosa (Cole,
1954).  Yowell (1951) also  reported, in a  patent  appli-
cation,  that  HEX has  antibacterial properties; standard
phenol   coefficients  for  Ebertnella  typhi   (Salmonella
 typhi) and  Staphylococcus aureus were 25 and 33, at 21 and
23 mg  HEX/litre,  respectively.  These  findings indicate
that  concentrations of HEX at or slightly above its aque-
ous  solubility  limit  are  toxic  to  several  types  of

    In  contrast,  tests  with other  microorganisms  have
shown some ability to withstand HEX exposure. Twenty-three
strains  of  organisms  (type unspecified),  when added to
aqueous  media containing HEX at  1000 mg/litre, were able
to  metabolize the compound to a varying degree.  Analysis
of  the medium after  14 days indicated  a HEX removal  of
2-76%,  depending  on the  organism  used (Thuma  et  al.,

    Rieck  (1977a) found no effects on natural populations
of  bacteria, actinomycetes, or fungi after a 24-day incu-
bation of a sandy loam soil treated with 1 or 10 mg HEX/kg
dry weight. It was concluded that no significant detrimen-
tal  effects  on  microbial populations  would result from
contamination of soils with these levels of HEX.

    The  effects  of  HEX on  three ecologically important
microbial  processes have been  reported (Butz &  Atallah,
1980).   Results  on  cellulose degradation  by the fungus
 Trichoderma   longibrachiatum indicated that a  suspension
of  HEX inhibited cellulose degradation at a concentration
of  1 mg/litre or more in a liquid medium.  The calculated
7-day  EC50   was 1.1 mg/litre.  Extrapolations for 1- and

3-day EC50   values were both reported to be 0.2 mg/litre.
The  decrease  in  toxicity  over  the  7-day  period  was
attributed to adaptation by  T. longibrachiatum.

    HEX  inhibited anaerobic sulfate reduction by the bac-
terium  Desulfovibrio desulfuricans when HEX was present in
suspension in a liquid medium. After a 3-h contact period,
growth  inhibition was observed  at HEX concentrations  of
10-100 mg/litre,  and there was no  growth at 500 or  1000
mg/litre.   Similarly, growth inhibition was observed at 1
and 10 mg/litre after a 24-h contact period, and there was
no growth at 50-1000 mg/litre.  HEX was considered  to  be
slightly   toxic  to  D.  desulfuricans (Butz   &  Atallah,

    The  third part of  the study by  these  investigators
(Butz  & Atallah, 1980) focused  on the effects of  HEX on
urea  ammonification by a mixed microbial culture in moist
soil.   The results indicated  that HEX concentrations  of
1-100 mg/kg  (dry weight) were not toxic to soil organisms
responsible  for urea ammonification. The EC50   increased
from  104 mg/kg at  day 1  to 1374 mg/kg  at day 14.   The
authors suggested that the low toxicity and  its  decrease
over  time in this experiment may have been due to adsorp-
tion  of the toxicant onto  soil particles, as well  as to
potential adaptation by the organism. Adsorption onto soil
particles may also account for the lack of toxicity in the
study of Rieck (1977a).

    Walsh  (1981) reported unpublished data on the effects
of HEX on four species of marine algae, obtained according
to  the method described by Walsh & Alexander (1980).  The
7-day  EC50    was  calculated as  the  concentration that
caused a 50% decrease in growth compared with the control,
as  estimated  by absorbance at  525 nm.  The  7-day  EC50
values  reported indicated a wide  range of susceptibility
among   the  species  tested.    Isochrysis   galbana  and
 Skeletonema   costatum were the most  susceptible species,
the average 7-day EC50 values being about 3.5 and 6.6 µg per
litre,  respectively.  The average  value for  Porphyridium
 cruentum was   30 µg/litre,    while  that  for  Dunaliella
 tertiolecta was   100 µg/litre.     Other  tests   with  S.
 costatum indicated that the direct algicidal effect of HEX
was less pronounced than its effect on growth.  After 48 h
of exposure to HEX at 25 µg/litre,   mortality,  as  indi-
cated  by  staining  and  cell  enumeration,  was  only 4%
(Walsh, 1983).

7.2.  Aquatic organisms

7.2.1.  Freshwater aquatic life

    Several studies are available on the effects resulting
from exposure of freshwater aquatic life to  various  con-
centrations of HEX.

    Results from acute toxicity tests with HEX  have  been
reported  for a number  of freshwater fish  species (Table
12).  The 96-h LC50   value for fathead minnow larvae in a
flow-through test with measured toxicant concentration was
7 µg/litre   (Spehar et al., 1977, 1979).  Values obtained
for  adult fathead minnows in static tests with unmeasured
toxicant  concentrations  ranged  from 59 to  180 µg/litre
(Henderson,  1956; Buccafusco & LeBlanc,  1977).  Reported
96-h  values for goldfish, channel  catfish, and bluegills
were also within this range (Buccafusco &  LeBlanc,  1977;
Podowski & Khan, 1979; Khan et al., 1981).

    Sinhaseni   et  al.  (1982)  reported  the  biological
effects  of HEX on rainbow trout  (Salmo gairdneri) exposed
to  130 µg  HEX/litre in a  non-recirculating flow-through
chamber.   Oxygen consumption, measured polarographically,
increased  by  193%  within  80 min  and  then   gradually
decreased  until the fish died  (after approximately 5 h).
Vehicle controls showed no effects after 76 h of exposure.
When  added  to  normal trout  mitochondria, HEX increased
basal  oxygen consumption.  The authors concluded that HEX
uncoupled oxidative phosphorylation.

    Sinhaseni  et al. (1983)  continued their research  on
the  respiratory effects of  HEX on intact  rainbow trout.
Acclimated rainbow trout were exposed to 130 µg  HEX/litre
in  a flow-through well-water circuit,  which was designed
to  allow  measurements  of oxygen  consumption  in  fish.
Again, HEX increased oxygen consumption rates (186 ± 24%),
the maximum rates being nearly the same as in the previous
experiment (approximately 84 min).  The oxygen consumption
decreased until death (after approximately 6.5 h). Control
trout,  exposed to the  same concentration of  the vehicle
(acetone)  used to disperse  HEX, showed no  changes.  The
authors reported profound respiratory stimulation, and HEX
appeared to uncouple oxidative phosphorylation.  Sinhaseni
et  al.  (1983) postulated  that  HEX intoxication  in the
intact animal may be due to increased  oxygen  consumption
and  impaired oxidative ATP  synthesis resulting from  the
mitochondrial uncoupling action of HEX.

Table 12.  Acute toxicity data for freshwater species exposed to HEX
Species                   Methoda        LC50 (µg/litre)b                 concentration  Comments           Reference
                                    24-h          48-h         96-h       (µg/litre)
Cladoceran                S,U       93.0          52.2         ND         32             17 °C, soft water  Vilkas (1977)
  Daphnia magna                      (78.9-109.6)  (44.8-60.9)

Cladoceran                S,U       130           39           ND         18             22 °C, soft water  Buccafusco &
  Daphnia magna                      (68-260)      (30-52)                                                   Leblanc (1977)

Fathead minnow            FT,M      NR            NR           7.0        3.7            25 °C, soft water  Spehar et al.
 (larvae, < 0.1 g)                                                                                          (1977, 1979)
  Pimephales promelas

Fathead minnow (1-1.5 g)  S,U       115           110          104        NR             Hard water,        Henderson
  Pimephales promelas                                                                     acetone soln.      (1956)
                                    93            78           78         NR             Soft water, 
                                                                                         acetone soln.         
                                    75            59           59         NR             Hard water, 
                                                                                         (no acetone)

Fathead minnow (0.72 g)   S,U       240           210          180        87             22 °C, soft water  Buccafusco &
  Pimephales promelas                (170-320)     (180-250)    (160-220)                                    Leblanc (1977)

Goldfish                  NR        NR            NR           78         NR             No details given   Podowski & Khan
  Carassius auratus                                                                                          (1979)

Channel catfish (2.1 g)   S,U       190           150          97         56             22 °C, soft water  Buccafusco &
  Ictalurus punctatus                (140-250)     (130-180)    (81-120)                                     Leblanc (1977)

Bluegill (0.45 g)         S,U       170           150          130        65             22 °C, soft water  Buccafusco &
  Lepomis macrochirus                (140-210)     (120-180)    (110-170)                                    Leblanc (1977)
a   S = static, FT = flow-through, U = unmeasured concentrations, M = measured concentrations.
b   Numbers in parentheses show 95% confidence interval.   ND = Not determined.   NR = Not reported.
    Spehar et al. (1977, 1979) conducted 30-day early-life
stage  flow-through  toxicity  tests with  fathead minnows
 (Pimephales   promelas) using  measured concentrations and
1-day-old  larvae.  The 96-h LC50  value was   7 µg/litre.
The  96-h  mortality  data  indicated  a  sharp   toxicity
threshold, such that 94% survival was observed  at  3.7 µg
per litre, 70% at 7.3 µg/litre,  and 2%  at  9.1 µg/litre.
At  the end of the  30-day exposure period, mortality  was
only  slightly higher, with 90%  survival at 3.7 µg/litre,
66%  at 7.3 µg/litre,   and  0% at 9.1 µg/litre.     These
results  indicated that the  median lethal threshold,  the
lowest  concentration  causing 50%  mortality, was reached
within  4 days.  In addition,  the HEX residues  found  in
fathead  minnows at the end  of the 30-day tests  were low
(< 0.1 µg/g),    and  a BCF  value  of < 11  was  reported
(Spehar  et al., 1979).   The authors concluded  that  the
toxicity  data and the BCF  values indicated that HEX  was
non-cumulative  in fish, i.e. it did not bioconcentrate in
fish  as a result of continuous low-level exposure to HEX.
The  growth rate of surviving larvae, measured in terms of
both  body length and  weight, did not  decrease  signifi-
cantly  at any of the concentrations tested, compared with
the controls. This was true even at 7.3 µg/litre,  a level
greater  than the calculated LC50   value.  Based on these
toxicity and growth data, Spehar et al. (1977, 1979)  con-
cluded  that 3.7 µg/litre  is the highest concentration of
HEX  that produces no  adverse effects on  fathead  minnow
larvae.  No other chronic toxicity data for any freshwater
species are available.

7.2.2.  Marine and estuarine aquatic life

    Among marine invertebrates, the 96-h LC50   values for
HEX  range from 7  to 371 µg/litre   (Table 13)  (US  EPA,
1980a).    Except  where  indicated,  these  results  were
obtained  from static tests with nominal concentrations of
HEX.   The highest LC50    by far was  for the  polychaete
 Neanthes   arenaceodentata,  which is an infaunal organism
living  in the sediment.   The two shrimp  species  tested
were more sensitive to HEX by a factor of 10 or more.

    The static LC50   value reported by US EPA (1980a) for
the grass shrimp,  Palaemonetes pugio, was slightly higher
than  that for the mysid shrimp,  Mysidopsis  bahia (Table
13). However, the LC50 for  the mysid shrimp was consider-
ably lower in a flow-through test than in the static test.

    Similarly,  the LC50   value was lower when calculated
from actual measurements of HEX concentrations in the test
solutions  (measured  concentration) than  when calculated
according  to  the  concentrations based  on amounts orig-
inally added to test solutions (nominal concentrations).

Table 13.  Acute toxicity data on estuarine marine 
organisms exposed to HEXa
Species                    Methodb   Salinity   96-h LC50c
                                     (o/oo)     (µg/litre)
Polychaete                 S,U       28         371
 Neanthes arenaceodentata                       (297-484)

Grass shrimp               S,U       22         42
 Palaemonetes pugio                             (36-50)

Mysid shrimp               S,U       24         32
 Mysidopis bahia                                (27-37)

Mysid shrimp               FT,U      24         12
 Mysidopsis bahia                               (10-13)

Mysid shrimp               FT,M      24         7
 Mysidopsis bahia                               (6-8)

Pinfish                    S,U       22         48
 Lagodon rhomboides                             (41-58)

Spot                       S,U       22         37
 Leiostomus xanthurus                           (30-42)

Sheepshead minnow          S,U       24         45
 Cyprinodon variegatus                          (34-61)
a   Adapted from: US EPA (1980a) and Mayer (1987).
b   S = static; FT = flow-through; U = unmeasured 
    concentrations; M = measured concentrations.
c   Numbers in parentheses show 95% confidence interval.

    The  acute toxicity values  for HEX were  similar  for
each of three estuarine and marine fish species tested (US
EPA,  1980a).   The static  96-h  LC50   values  based  on
unmeasured concentrations for spot, sheepshead minnow, and
pinfish varied only between 37 and 48 µg/litre (Table 13).

7.3.  Terrestrial organisms and wildlife

    In  a USA patent application,  HEX was reported to  be
nontoxic  to plants in concentrations  at which it was  an
effective  fungicide (Yowell, 1951).  Test  solutions were
prepared  by adding HEX at various proportions to attaclay
and  a wetting agent, and they were then mixed with water.
The  concentrations of HEX applied to plants as an aqueous
spray   were  0.1,  0.2,  0.5,  and  1.0%.  Slight  injury
(unspecified)  to  Coleus blumei was reported at  1.0% HEX,
but lower concentrations were not harmful.  Similarly, HEX
was  added to horticultural spray oil and an emulsifier at

various proportions and then mixed with water. The concen-
tations of HEX in the prepared spray were 0.25  and  0.5%.
No  injury  to  C.  blumei was observed  at  these  concen-
trations.  No data are available concerning the effects of
HEX  on amphibians, reptiles, birds, or mammals other than
those routinely used in laboratory testing.

7.4.  Population and ecosystem effects

    The ecological effects of HEX have not been studied at
the ecosystem, population, or community levels.


8.1.  Acute toxicity studies

8.1.1.  Acute oral, inhalation, and dermal toxicity

    The  data from acute  toxicity studies using  HEX  are
summarized  in  Table 14.  Caution should  be exercised in
comparing the various studies.  The  acute toxicity  (LD50
and  LC50)   may be affected  not only by the  species and
age  of the animals  used in the  experimental tests,  but
also  by the strain. In  addition, the purity of  the com-
pound  and the nature of  the contaminants may affect  the
toxicity, as can the experimental method and  the  vehicle
used.   These details (when specified  by the researchers)
have been summarized in the table.

    For the rat, oral LD50   values ranged from 425 to 926
mg/kg  for males, and from  315 to 926 mg/kg for  females.
Values for mice and rabbits were within the same range.

    Acute   inhalation   experiments   involved   exposure
durations from 3.5 to 4 h, and LC50   values for male rats
ranged  from 18.1 to 35.0 mg/m3   (1.6 to 3.1 ppm) and for
female  rats from 35.0  to 40.0 mg/m3   (3.1  to 3.5 ppm).
The  mouse, rabbit, and guinea-pig values ranged from 23.7
to 80.2 mg/m3 (2.1 to 7.1 ppm).

    There  are  few  data available  on  dermal  toxicity.
LD50   values of < 200 mg/kg in male rabbits  and  340-780
mg/kg in females have been reported.

    In spite of variations in LD50   values in the differ-
ent  studies, these data  suggest that HEX  is  moderately
toxic when administered orally.  The acute toxicity of HEX
by  the dermal route  is quite similar  to its acute  oral
toxicity.   HEX is much more toxic by the inhalation route
of exposure than by the dermal or oral routes.

8.1.2.  Eye and skin irritation

    IRDC (1972) tested HEX for eye irritation  by  instil-
ling 0.1 ml HEX into the eyes of New Zealand white rabbits
for 5 min or 24 h before washing.  All the rabbits died on
or  before the ninth day of the observation period.  Treon
et al. (1955) reported HEX to be a primary  skin  irritant
in  rabbits (strain unspecified)  at a dose  level of  250
mg/kg, and IRDC (1972) reported HEX to be a  dermal  irri-
tant because of the oedema that appeared after application
of  0.5 ml HEX.  In  this study, intense  discoloration of
the  skin was noted.  In the study of Treon et al. (1955),
monkeys  (strain unspecified) were  also tested, and  dis-
coloration of the skin was noted even at low  doses  (0.05
ml of 10% HEX) (Table 15).

Table 14.  Acute toxicity studies of HEX
Species (strain) age    Route (vehicle)  Resultsa        Reference
 Oral LD50

Rat (unspecified)       oral gavage      M: 510 mg/kg    Treon et al.
  young adult           (5% solution     F: 690 mg/kg    (1955)
                        of peanut oil)

Rat (Charles River CD)  oral gavage      M + F: 926      IDRC (1968)
  young adult           (corn oil)       mg/kg

Rat (Sprague-Dawley)                     M + F: 651      Dorough (1979)
  young adult                            mg/kg

Rat (Fischer-344)       oral gavage      M: 425 mg/kg    SRI (1980a)
  weanling              (corn oil)       F: 315 mg/kg

Mouse (unspecified)                      M + F: 600      Dorough (1979)

Mouse (B6C3F1)          oral gavage      M + F: 680      SRI (1980a)
  weanling              (corn oil)       mg/kg

Rabbit (Albino, strain  oral gavage      F: 640 mg/kg    Treon et al.
  unspecified) adult    (5% peanut oil)                  (1955)

 Dermal LD50

Rabbit (unspecified)    skin painted     F: 780 mg/kg    Treon et al.
  adult                                                  (1955)

Rabbit (unspecified)    skin painted     M: < 200 mg/kg  IDRC (1972)
  adult                                  F: 340 mg/kg

 Inhalation LC50

Rat (Carworth)          inhalation       3.5-h LC50      Treon et al.
  young adult                            M + F: 35.0     (1955)
                                         mg/m3 (3.1 ppm)

Rat (Sprague-Dawley)    inhalation       4.0-h LC50      Rand et al.
  young adult                            M: 18.1 mg/m3   (1982a)
                                         (1.6 ppm)         
                                         F: 39.6 mg/m3 
                                         (3.5 ppm)

Mouse (unspecified)     inhalation       3.5-h LC50      Treon et al.
  young adult                            M + F: 23.7     (1955)
                                         mg/m3 (2.1 ppm)

Table 14 (contd.)
Species (strain) age    Route (vehicle)  Resultsa        Reference
Rabbit (unspecified)    inhalation       3.5-h LC50      Treon et al.
  adult                                  F: 58.8 mg/m3   (1955)
                                         (5.2 ppm)         

Guinea-pig              inhalation       3.5-h LC50      Treon et al.
  (unspecified) adult                    M + F: 80.2     (1955)
                                         mg/m3 (7.1 ppm)
a   M = male; F = female.
Table 15. Primary eye and dermal irritation
Study           Species (strain)      Results                        Reference
Primary eye     Rabbit (New Zealand   Severe eye irritant (0.1       IRDC (1972)
irritation      white) adult          ml for 5 min or 24 h); all
                                      died by day 9 of study

Primary dermal  Rabbit (unspecified)  Moderate skin irritant         Treon et al.
irritation      adult                 (250 mg/kg); one               (1955)

Primary dermal  Rabbit (New Zealand   Severe skin irritant           IRDC (1972)
irritation      white) adult          (200 mg/kg); all males died

Primary dermal  Monkey (unspecified)  Mild skin discoloration        Treon et al.
irritation      adult                 (0.05 ml of 10% HEX solution)  (1955)
    Shell  Research Limited conducted a study of the skin-
sensitizing  potential of 98.8%  pure HEX (Shell  Research
Limited,  1982).   Guinea-pigs  (310-370g) were  placed at
random  into single sex groups of 10 animals and housed in
groups of five animals. Range-finding tests were conducted
to  determine the concentrations  of test material  to  be
used  for  intradermal  induction, topical  induction, and
topical  challenge.  Two male  and two female  guinea-pigs
were  injected intradermally on  each side of  the midline
with 0.1 ml of several dilutions (0.5, 1, 5, and 10 mg HEX
per ml HEX corn oil).  Filter paper patches with 0.3 ml of
a  1%  or 2%  dilution of test  material in corn  oil were
applied to two other groups. On the basis of  the  results
of  the range-finding studies, the following tests and HEX
concentrations  were selected for use:  intradermal induc-
tion,  0.5 mg/litre; topical induction, 20.5 mg/litre; and
topical  challenge, 10 mg/ml (all  in corn oil).   In  the
sensitizing  test, all four  animals given an  intradermal
injection  of 0.5 mg HEX/ml suffered  necrosis, while top-
ical  applications at 10 or  20.5 mg/litre produced slight
redness  or no difference from surrounding skin.  However,
all  20 test animals showed positive responses 24 and 48 h

after  removal of the challenge  patches.  The researchers
concluded that HEX is a skin sensitizer.

8.2.  Short-term exposure

8.2.1.  Oral

    In a range-finding study using groups of five male and
five female Fischer-344 rats, there were no deaths when 12
doses  of 25, 50, or 100 mg/kg were given in 16 days (SRI,
1980b).   With the same dosing  schedule, one out of  five
males  and four out of five females died when the dose was
200 mg/kg, and five out of five males and four out of five
females  died when  the dose  was 400 mg/kg.  In the  same
study, B6C3F1   mice died when given doses of 400  or  800
mg/kg,  but not when given doses of 50, 100, or 200 mg/kg.
Both rats and mice exhibited pathological changes  of  the
stomach wall at all but the lowest dose level.

    The  short-term toxicity of HEX is summarized in Table
16. These short-term toxicity studies on B6C3F1   mice and
Fischer-344  rats  were  conducted by  SRI (1981a,b) under
contract  with the National Toxicology  Program (NTP), and
the results were reported by Abdo et al. (1984).   In  the
mouse  study (SRI, 1981a),  HEX (94.3-97.4% pure)  in corn
oil was administered by gavage at dose levels of  19,  38,
75, 150, and 300 mg/kg to 10 mice of each sex, 5 days/week
for  13 weeks (91 days).  At  the highest dose  level (300
mg/kg), all 10 male mice died by day 8 and  three  females
died by day 14.  In female mice, the liver  was  enlarged.
Toxic  nephrosis in females at  doses of 75 mg/kg or  more
was  characterized by distensions in  the proximal convol-
uted tubules, with basophilia in the inner  cortical  zone
and  cytoplasmic vacuolization.  However, male mice admin-
istered 75 mg/kg or more did not show these effects.  Dose
levels  of 38 mg/kg or  more caused lesions  in the  fore-
stomach,  including ulceration in both  males and females,
as  well as increased kidney  and liver weights.  The  no-
observed-adverse-effect level (NOAEL) in mice was 19 mg/kg
and  the lowest-observed-adverse-effect level  (LOAEL) was
38 mg/kg.

    In  the rat study  (SRI, 1981b), HEX  in corn oil  was
administered by gavage at dose levels of 10, 19,  38,  75,
and  150 mg/kg to groups of 10 male and female F-344 rats.
At  38 mg/kg or more,  mortality and toxic  nephrosis were
observed in both males and females.  The male rats treated
with  19 mg/kg showed no  significant effects, but  female
rats had lesions in the forestomach.  Similar lesions were
observed  in males  given 38 mg/kg  or more.  There was  a
dose-related  depression of body weight  gain (relative to
the  controls) and female  rats had increased  kidney  and
liver  weights.  The NOAEL in  rats was 10 mg/kg, and  the
lowest-observed-effect level (LOEL) was 19 mg/kg.

    A  summary  of the  results  of these  two experiments
appears in Table 17.

Table 16.  Short-term toxicity of HEX
Study        Species   Dose                    Results             Effects at LOEL         Reference
                                                                   or lowest dose
90-day       rat       10, 19, 38, 75, and     NOAEL: 10 mg/kg     lesions of forestomach  SRI (1981b)
feeding                150 mg/kg (by gavage)   LOEL: 19 mg/kg      in female rats at 
study                                                              19 mg/kg

14-week      rat       0.11, 0.56, and 0.226   NOEL: 0.226 mg/m3   no statistically        Rand et al. 
inhalation             mg/m3 (5 days/week)     LOEL: NE            significant effects     (1982a)

14-week      monkey    0.11, 0.56, and 0.226   NOEL: 0.2 ppm       no effects noted        Alexander 
inhalation             mg/m3 (5 days/week)     LOEL: NE                                    et al.
study                                                                                      (1980)
NE = not established.
NOAEL = no-observed-adverse-effect level.
NOEL = no-observed-effect level.
LOEL = lowest-observed-effect level.

Table 17.  Toxicological parameters for mice and rats administered technical grade HEX
in corn oil by gavage for 91 daysa
Species    Sex     Dose     Mortality  Relative   Forestomach   Forestomach   Toxic
(strain)           (mg/kg)             weight     inflammation  hyperplasia   nephrosis
Mice       male    0        1/10                  0/10          0/10          0/10
 (B6C3F1)          19       0/10       + 36%      0/10          0/10          0/10
                   38       0/10       + 9%       2/10          2/10          0/10
                   75       0/10       - 9%       7/10          8/10          0/10
                   150      0/10       - 45%      7/10          9/10          0/10
                   300      10/10                 7/10          8/10          0/10

Mice       female  0        0/10                  0/10          0/10          0/10
 (B6C3F1)          19       0/10       + 13%      0/10          0/10          0/10
                   38       0/10       - 13%      2/9           2/9           0/9
                   75       0/10       - 13%      6/10          9/10          10/10
                   150      0/10       - 25%      10/10         10/10         10/10
                   300      3/10       - 38%      7/9           9/9           7/10

Rats       male    0        3/10                  0/10          0/10          0/10
 (F-344)           10       1/10       - 4%       0/10          0/10          0/10
                   19       1/10       - 8%       0/10          0/10          0/10
                   38       1/10       - 20%      4/10          5/10          10/10
                   75       3/10       - 49%      9/10          9/10          9/10
                   150      7/10       - 57%      8/9           8/9           8/10

Rats       female  0        1/10       0%         0/10          0/10          0/10
 (F-344)           10       2/10       + 4%       0/10          0/10          0/10
                   19       1/10       - 5%       2/10          2/10          0/10
                   38       1/10       - 2%       2/10          5/10          10/10
                   75       3/10       - 30%      9/10          9/10          10/10
                   150      5/10       - 33%      9/10          9/10          10/10
a   From: SRI (1981a,b).
b   Relative weight gain was calculated as follows:
      Dose group value - control group value
      --------------------------------------  x 100
              Control group value

8.2.2.  Short-term inhalation toxicity

    Rand et al. (1982a) conducted a range-finding study in
which  groups of 10 male and 10 female Sprague-Dawley rats
were  exposed  to atmospheres  of  0.25, 1.24,  or 5.65 mg
HEX/m3    (0.022, 0.11, or 0.5 ppm),  6 h/day, 5 days/week
for a total of 10 exposures. Nine male rats and one female
rat  exposed to 5.65 mg/m3    were moribund after  five to
seven exposures.  These rats had dark red  eyes,  laboured
breathing, and pale extremities. There were no mortalities
in  the other exposure groups.  However, the males in  the
medium- and  high-dose groups lost weight during the study
and reduced mean liver weights and pathology  were  noted.
The  NOAEL for HEX exposure  in this study was  0.25 mg/m3
and the LOEL was 1.24 mg/m3.

    Fourteen-week inhalation studies have been carried out
on  rats and monkeys (Alexander et al., 1980; Rand et al.,
1982a,b)  and  the  results are  summarized  in  Table 16.
Groups   of  40 male  and  40 female  Sprague-Dawley  rats
weighing  160-224 g  and  groups of  12 Cynomolgus monkeys
weighing  1.5-2.5 kg were exposed to  HEX, 6 h/day, 5 days
per  week, for 14 weeks.  Levels of exposure were 0, 0.11,
0.56, and 2.26 mg/m3   (0, 0.01, 0.05, and  0.20 ppm).  In
monkeys,  there  were  no  mortalities,  adverse  clinical
signs,  weight  gain changes,  pulmonary function changes,
eye  lesions,  haematological changes,  clinical chemistry
abnormalities,  or histopathological abnormalities  at any
dose level tested. Thus, the NOEL for monkeys was at least
2.26 mg/m3    for this exposure  period, but the  LOEL was
not established. Male rats had a transient  appearance  of
dark-red eyes at 0.56 and 2.26 mg/m3.   At 12 weeks, there
were  marginal but not statistically significant increases
in  haemoglobin  concentration  and erythrocyte  count  in
males  exposed  to  0.11 mg/m3,   females  exposed to 0.56
mg/m3,  and  males  and females  exposed  to   2.26 mg/m3.
There were small but not statistically significant changes
in  mean liver weight  of all groups  of treated rats  and
similar  changes in the kidneys  of all treated males.  No
treatment-related  abnormalities  in  gross  pathology  or
histopathology  were observed.  On this basis, the NOEL in
rats was 2.26 mg/m3, but the LOEL was not established.

    In a further study by Rand et al. (1982b),  no  ultra-
structural  changes were observed in monkeys that could be
attributed to the inhalation of HEX vapour.  Exposure  was
identical  to that  of the  previous study  (Rand et  al.,
1982a).   There was a statistically significant (P < 0.01)
increase  in the mean number  of electronlucent inclusions
in  the apex and base  of the Clara cells  in exposed ani-
mals,  as compared with  the controls.  According  to some
researchers (Evans et al., 1978), Clara cells  respond  to
injury  by regression to a more primitive cell type.  Rand
et  al.  (1982b) noted  that  some of  the ultrastructural
changes  in  the exposed  animals  resembled those  of the
Evans  study.  It is not  known what effect these  changes
might   cause.   The  Clara   cell  contributes  important
materials  to the extracellular  lining of the  peripheral
airways,  and if this effect of HEX vapour causes a change
in  the  content of  the  contributed material,  then  the
extracellular lining may be altered and breathing  may  be
subsequently  impaired (Rand et al.,  1982b).  This obser-
vation  of  lung effects  coincides  with those  of  other
researchers  (Dorough,  1979,  1980; Lawrence  &  Dorough,
1981,  1982).  Furthermore, in inhalation studies with HEX
occasional  statistically  significant  increases  in  the
haemoglobin level and red blood cell counts of  rats  have
been  noted, which may be manifestations of the impairment
of respiratory functions.

    In  1984,  the  US National  Toxicology  Program (NTP)
completed  a  short-term,  90-day HEX  inhalation study on
B6C3F1   mice and F-344 rats (NTP, 1984a,b).  In the basic
study,  ten rats and ten  mice of each sex  were placed at
random into five exposure and control groups. The rats and
mice were exposed to nominal concentrations of 0.45, 1.70,
4.52,  11.3, or 22.6 mg/m3   (0.04, 0.15, 0.4, 1.0, or 2.0
ppm) for 6 h/day, 5 days/week for 13 weeks.  In the female
mouse  study, 6  out of  10 of the  control animals  died,
while none of the animals in the male  control  population
died.   The six animal deaths in week 7 were attributed to
a defective feeder insert.  Mortality in both the rats and
mice was high in the two highest-dose groups; all rats and
mice in these groups died in the first five weeks  of  the
study.   Posterior paresis and listlessness  were observed
in  mice at 4.52 and 11.3 mg/m3.   Compound-related histo-
pathological  alterations were observed in the respiratory
tracts of male and female mice exposed to  1.7 mg/m3    or
more.    These  changes  included:  necrosis,   acute  and
chronic  inflammation, hyperplasia or  squamous metaplasia
of the nasal, laryngeal, tracheal, bronchial, and bronchi-
olar  epithelia  of  the affected  animals.   No compound-
related  effects were observed in mice at the lowest dose,
and  so this  level could  be considered  the  NOEL  (NTP,

    Clinical  signs  resulting from  HEX exposure included
posterior  paresis in all  rats exposed to  1.7 mg/m3   or
more,  listlessness in all rats exposed to 4.52 mg/m3   or
more, and eye irritation and respiratory distress  in  all
rats  exposed to 11.3 mg/m3   or  more. As in the  case of
mice,  HEX caused significant histological  alterations in
the respiratory tracts of rats at the two  highest  doses.
Changes  of  a less-marked  degree  were observed  in  the
respiratory  tracts  of  rats receiving  4.52 mg/m3.    No
compound-related  changes were seen  in any organ  of male
and  female rats exposed to  the lowest dose, and  so this
level could be considered the NOEL. In addition, compound-
related  effects of a secondary stress-related nature were
seen  in a number of other organs of rats of both sexes at
the  two highest doses. These  includes lymphoid depletion
of the spleen and thymus, degeneration of the seminiferous
tubules  and  decreased  lytoplasmic vacuolization  of the
adrenal cortex.

    Some  basic  clinical  pathology  and   histopathology
examinations   were  undertaken  simultaneously   in  both
studies (NTP, 1984a,b).  All effects were similar to those
noted  in the previous toxicity studies.  In the rat study
(NTP,  1984b),  HEX  nephrotoxicity was  examined  in more
depth.  HEX was not found  to be nephrotoxic at  these ex-
posure levels, nor did it appear that it was myelotoxic.

8.2.3.  Short-term dermal toxicity

    No short-term dermal toxicity studies are available.

8.3.  Long-term exposure

8.3.1.  Long-term oral toxicity

    No long-term oral toxicity studies have been reported.

8.3.2.  Long-term inhalation toxicity

    In  view of the  absence of long-term  studies on  the
inhalation  of HEX, the  following studies were  examined.
Treon  et al. (1955)  exposed guinea-pigs, rabbits,  rats,
and  mice to  a HEX  (89.5% pure)  concentration  of  3.73
mg/m3     (0.33 ppm),  7 h/day,  5 days/week,   for  25-30
exposure  days.   The  guinea-pigs survived  30 exposures,
whereas  rats and mice did not survive five exposures, and
four  out  of six  rabbits  did not  survive 25 exposures.
Using  a  lower concentration  of 1.70 mg/m3   (0.15 ppm),
guinea-pigs,  rabbits, and rats survived 150 7-h exposures
over a 7-month period.  This level was too high to conduct
a long-term study in mice since four out of  five  animals
did not survive. The rats, guinea-pigs, and rabbits toler-
ated 1.7 mg/m3   and did not exhibit any treatment-related
effects. Thus, the NOEL for rats, guinea-pigs, and rabbits
was  1.7 mg/m3   over the 7-month period.  Due to the high
mortality, a NOEL for mice could not be established.

    A  long-term (30 weeks) inhalation study  in rats with
technical  grade  HEX  (96% pure  with hexachlorobuta-1,3-
diene  and octachlorocyclopentene as impurities)  was con-
ducted by the Shell Toxicology Laboratory (D.G.  Clark  et
al.,  1982).  Four groups of  eight male and eight  female
Wistar  albino rats were exposed to HEX at nominal concen-
trations of 0, 0.56, 1.13, and 5.65 mg/m3   (0, 0.05, 0.1,
and  0.5 ppm), 6 h/day, 5 days/week, for 30 weeks and were
observed  for  a  14-week  recovery  period  without   HEX
exposure.  At the highest dose level, four males  and  two
females died.  In males, there was depressed  body  weight
gain  at the highest dose, relative to controls, beginning
at  7 weeks  of  exposure and  persisting  throughout  the
remainder of the study.  Females in the  two  highest-dose
groups had lower body weights at the end of  the  recovery
period  than did the controls.  At the highest dose, there
were  pulmonary  degenerative  changes, ranging  from epi-
thelial  hyperplasia  and oedema  to epithelial ulceration
and necrosis, in both sexes, the males being affected more
severely.   There were also  mild degenerative changes  in
the  liver  (bile  duct hyperplasia  and inflammatory cell
infiltration)  and kidneys (protein  casts in tubules  and
pigmented  cortical  tubules) in  a  few rats,  and kidney
weights  were significantly increased in the females at 30
weeks.  After 30 weeks of study,  no biologically signifi-
cant  toxicity was noted in  animals that were exposed  to
0.56  or 1.13 mg/m3.   Thus, the  NOEL in rats exposed  to
HEX  vapour in this  study (6 h/day, 5 days/week,  for  30
weeks) was 0.56 mg/m3, and the LOEL was 1.13 mg/m3.

    A  long-term  inhalation  study by  the National Toxi-
cology  Program  started  in  January  1986.  The   animal
exposure  has been completed and results will be published
as soon as the pathology review is completed.

8.3.3.  Long-term dermal toxicity

    No   long-term  dermal  toxicity  studies   have  been

8.3.4.  Principal effects and target organs

    Repeated  exposure of several animal species to levels
of HEX vapour in the range of 1.13 to  2.26 mg/m3 (0.1-0.2
ppm)  has  been  found  to  cause  pulmonary  degenerative
changes (Treon et al., 1955; D.G. Clark et al., 1982; Rand
et  al.,  1982a,b).  In  addition,  Treon  et  al.  (1955)
reported  diffuse  degeneration  of the  brain, heart, and
adrenal  glands  and  necrosis  of  the  liver  and kidney
tubules,  together  with  severe pulmonary  hyperaemia and
oedema.  In many instances, acute bronchitis and intersti-
tial pneumonitis also occurred. Necrosis of the epithelium
of  the  primary,  secondary,  and  tertiary  bronchi  was
observed.   At  later stages,  reacting inflammatory cells
migrated into the wall and the mucosa of the  bronchi  and
alveoli. In rabbits, the walls of the alveoli were covered
by a hyaline or fibrinoid membrane.  Possibly, some of the
changes  found  by  Treon et  al.  (1955)  were caused  by
impurities  in the HEX preparation.  Acute exposure by the
oral and dermal routes also affects the respiratory system
(Kommineni,  1978; SRI, 1980a).  Death from acute exposure
by any tested route seemed to be associated  with  respir-
atory failure (Lawrence & Dorough, 1982).

    There  are insufficient data to identify the site that
is the most sensitive to prolonged, repeated  exposure  to
HEX.   In comparing routes of  administration, researchers
found  that  damage to  the  lungs occurred  regardless of
which route was used (Lawrence & Dorough, 1982).  When HEX
is  administered orally to animals, the kidneys may be the
most sensitive site, since short-term dosing of  rats  and
mice was found to cause nephrosis, especially  in  females
(SRI,  1981a,b).  Although  the oral  route may  not be  a
significant route of exposure for human beings,  the  fact
that the kidneys are a possible target organ in short-term
exposure  indicates  that  low-level,  prolonged  systemic
exposure  from any ambient  route may affect  the kidneys.
The liver has also been shown, in several of  the  labora-
tory studies, to be affected by HEX.

    The  available  literature  does not  cite  any single
mechanism  to explain HEX toxicity.   HEX vapour irritates
the  respiratory  tract,  leading to  death by respiratory
failure  after bronchopneumonia (D.G. Clark et al., 1982).

The  degenerative changes that  have been observed  in the
liver and kidneys are mild and unlikely to  contribute  to
the chemical's lethality (NAS, 1978; SRI, 1980a,b).

    The  difficulty in studying  HEX because of  its  high
reactivity  and  volatility  has also  created problems in
identifying  its metabolites.  Several questions remain as
to whether the same metabolites are formed  after  various
routes  of exposure and whether it is the administered HEX
or  its metabolites that cause the lung injuries seen with
various  dosing regimens.  Furthermore, the strong ability
of  HEX  to  interact  with  other  compounds,  especially
organic molecules, can lead to many other effects, such as
haemoglobin  binding. Little is  known about the  interac-
tions  of HEX  with other  chemicals in  animal  or  human

8.4.  Developmental and reproductive toxicity

    The teratogenic potential of HEX has been evaluated in
pregnant  Charles River CD-1  rats that were  administered
HEX (98.25%) in corn oil, by gastric intubation,  at  dose
levels of 3, 10, and 30 mg/kg per day from days 6 to 15 of
gestation. A control group received the vehicle (corn oil)
at a dose volume of 10 ml/kg per day.  All the  rats  sur-
vived, and there was no difference in mean  maternal  body
weight  gain between the dosed groups and controls.  There
were no differences in the mean number  of  implantations,
corpora lutea, live fetuses, mean fetal body  weights,  or
male/female  sex ratios among any of the groups, and there
were  no statistical differences in malformation or devel-
opmental  variations,  compared  with the  controls,  when
external,  soft  tissue,  and skeletal  examinations  were
performed (IRDC, 1978).

    Murray  et al. (1980) evaluated the teratogenic poten-
tial  of HEX  (98%) in  CF-1 mice  and New  Zealand  white
rabbits.  Mice were dosed at 0, 5, 25, or 75 mg HEX/kg per
day by gavage during days 6-15 of gestation, while rabbits
received the same dose during days 6-18 of gestation.  The
fertility of the treated mice and rabbits was not signifi-
cantly  different from that of the control groups.  In the
mice,  there was no evidence of maternal toxicity, embryo-
toxicity,  or  teratogenic  effects.  A  total  of 249-374
fetuses  (22-33 litters) was examined in  each dose group.
In rabbits, maternal toxicity was noted at a dose level of
75 mg/kg  (diarrhoea,  weight  loss, and  mortality),  but
there  was no evidence of  maternal toxicity at the  lower
levels.  There  were no  embryotoxic  effects at  any dose
level.  Although there was a two-fold increase  over  con-
trols  in the  proportion of  fetuses with  13 ribs at  75
mg/kg,  this was considered to  be a minor skeletal  vari-
ation.  The authors concluded that HEX was not teratogenic
at the levels tested (Murray et al., 1980).

    Chernoff & Kavlock (1982) tested 28 compounds, includ-
ing  HEX, by an  in vivo screening procedure.  According to
the  researchers, the underlying hypothesis  was that most
prenatal  insults would manifest themselves postnatally as
reduced  viability  and/or  impaired growth.   Twenty-five
Oravid CD-1 mice were administered HEX orally at  or  near
the  maternal minimal tolerated  dose (MTD).  The  MTD was
considered to be that dose resulting in either significant
weight  reduction during the treatment  period, mortality,
or  other signs of toxicity.  There were no differences in
maternal  weight gain, number of live offspring or average
weight  between the HEX-treated animals  and controls when
HEX was administered orally for 8-12 days at 45 mg/kg.

    Gray  & Kavlock (1984) extended the observation period
proposed by Chernoff & Kavlock (1982, 1983) to 250 days to
determine  whether  neonatal  weight reductions  persisted
throughout life and whether other serious abnormalities or
mortality  resulted from exposure  to HEX.  CD-1  pregnant
mice were orally exposed to HEX (45 mg/kg) on days 8 to 12
of  gestation, which is within the period of major embryo-
nic organogenesis.  Females were weighed throughout dosing
and  on day 19 of gestation.  They were allowed to deliver
and the litters were counted and weighed at 1  and  3 days
of  age.  The animals  were observed at  approximately 250
days  of age.  During the postmortem examination of males,
body  weight and the weights of the liver, testes, seminal
vesicles,  and right kidney  were recorded.  HEX  did  not
produce   any   statistically  significant   developmental
effects in this study.

    Studies  on the teratogenic  potential of inhaled  HEX
were not found in the review of the scientific literature.

8.5.  Mutagenicity

    Goggelman et al. (1978) found that HEX was  not  muta-
genic, either before or after liver microsomal activation,
at  2.7 mmol/litre  in  an  Escherichia   coli K12   back-
mutation system.  In this test there was a 70% survival of
bacteria  at 72 h. HEX  was not tested  at higher  concen-
trations because it was cytotoxic to  E.  coli.  A previous
report from the same laboratory (Greim et al., 1977) indi-
cated   that  HEX  was  also  non-mutagenic  in  Salmonella
 typhimurium  strains TA1535 (base-pair mutant) and TA1538
(frame-shift  mutant)  after liver  microsomal activation.
However,  no  details  of the  concentrations  tested were
given.   Although tetrachlorocyclopentadiene is  mutagenic
in these systems, probably through metabolic conversion to
the dienone, it appears that the chlorine atoms at the C-1
position of HEX hinder metabolic oxidation to  the  corre-
sponding acylating dienone (Greim et al., 1977).

    A  study conducted by the  Industrial Bio-Test Labora-
tories  (IBT, 1977) also suggested  that HEX is not  muta-
genic  in  S. typhimurium.  Both liquid HEX and its vapour
were  tested with and  without metabolic activation.   The
vapour  test was carried out in desiccators with the TA100
strain  of  S.  typhimurium  only.  It is  not clear  from
vapour  test  data  that  sufficient  amounts  of  HEX  or
adequate exposure times (30, 60, and 120 min)  were  used.
Longer  exposures in  the presence  of HEX  vapour may  be
necessary for a potential mutagenic effect to be seen.

    At  concentrations  of  up  to  1.25 mg/litre  in  the
presence  of an S-9 liver  activating system, HEX was  not
mutagenic  in the mouse lymphoma mutation assay. Mutageni-
city  could  not  be evaluated  at  higher  concentrations
because  of  the  cytotoxicity of  HEX  (Litton Bionetics,
Inc., 1978a). This assay uses L5178Y cells that  are  het-
erozygous  for thymidine kinase (TK+/-) and are sensitive.
The  mutation is scored by  cloning with bromodeoxyuridine
in the absence of thymidine.  HEX is highly toxic to these
cells, particularly in the absence of an activating system
(at  0.04 ml/litre),  and the  positive control, dimethyl-
nitrosamine, was mutagenic at 0.5 ml/litre.

    Williams  (1978) found that HEX (10-6   mol/litre) was
inactive  in  the liver  epithelial culture (hypoxanthine-
guanine-phosphoribosyl  transferase locus) mutation assay.
At 10-5   mol/litre it also failed to stimulate DNA repair
in hepatocyte primary cultures. Negative results were also
obtained  in an additional unscheduled DNA synthesis assay
(Brat, 1983).

    One  study  provided  by the  US  National  Toxicology
Program (NTP) (Haworth et al., 1983) demonstrated  a  lack
of  mutagenicity  of HEX  (98%  pure). In   S.  typhimurium
strains   TA98, TA100, TA1535, and TA1537, levels of up to
3.3 µg/plate    were not mutagenic without activation, and
levels  of up to  100 µg/plate   were not  mutagenic after
microsomal  activation.  Higher levels could not be tested
because  of excessive cell dealth. Zimmering et al. (1985)
tested  Drosophila by  the sex-linked recessive lethal test
(SLRL), either by feeding doses of 40 ppm for 3 days or by
giving  a single injection of 2000 ppm or 3000 ppm (volume
not  specified). The vehicle  used was 10%  ethyl alcohol,
which  did not  totally dissolve  the HEX.  HEX (98%)  was
first  assayed in the  SLRL test in  adult feeding  exper-
iments.  When negative results were obtained, the chemical
was  retested by injecting < 1  day-old Canton-S wild-type
 Drosphila  males.  The results of the injection test were
reported to be inconclusive.

    HEX has also been assayed in the mouse dominant lethal
test (Litton Bionetics, Inc., 1978b).  In this assay, 0.1,
0.3,  or 1.0 mg HEX/kg  was administered by  gavage to  10
male  CD-1 mice for  5 days and the  mice were then  mated

throughout spermatogenesis (7 weeks). This test determines
whether  the compound induces lethal genetic damage to the
germ  cells of males.  There  was no evidence of  dominant
lethal activity, at any dose level, based on any parameter
(e.g.,  fertility  index,  implantations  per   pregnancy,
average resorptions per pregnancy).

8.6.  Cell transformation

    The  ability of HEX to  induce morphological transfor-
mation  of BALB/3T3 cells  in  vitro has been studied  by
Litton Bionetics, Inc. (1977).

    The  selection  of test  doses  was based  on previous
cytotoxicity  tests  using a  wide  range of  HEX  concen-
trations  at 0.0, 0.01,  0.02, 0.039, 0.078,  and 0.156 mg
per litre. The cultures were exposed for 48 h,  which  was
followed  by  an  incubation  period  of  3-4 weeks.   The
cultures were observed daily. The doses selected allowed a
cell  survival of 80-100% compared  with controls (solvent
only).  This high survival rate permitted an evaluation of
 in   vitro  malignant transformation  in cultures treated
with HEX as compared with the solvent controls.  3-Methyl-
cholanthrene at a dose level of 3 mg/litre was used  as  a
positive  control.   Results  indicated that  HEX  was not
responsible for cell transformation.

8.7.  Carcinogenicity

    Bioassays of HEX for possible carcinogenicity have not
been  conducted.  As noted previously (section 8.3.2), the
NTP  has completed a study  on HEX for carcinogenicity  by
the  inhalation route in  rats and mice,  but the  results
were not available when this monograph was being prepared.


9.1.  General population exposure

    There is very little detailed information available on
the  human  health effects  of  HEX exposure.  Acute human
exposure has been reported in homes near waste sites where
disposal  of HEX has  occurred (C.S. Clark  et al.,  1982;
Elia et al., 1983).  The odour threshold has  been  stated
to be 1.92 µg/m3     (0.17 ppb), but there appears  to  be
great individual variation. According to a study completed
by  the  A.D.  Little  Co.  for  the  Occidental  Chemical
Corporation,  the 100% panel recognition concentration was
1.92 µg/m3     (0.17 ppb v/v)a,   but the study design and
methodology were not reported. The US EPA (1982) estimated
that  exposure of  the general  population to  HEX in  air
and/or water would be extremely low.

    Treon  et  al.  (1955)  reported  that  members  of  a
research  group conducting toxicity tests  developed head-
aches  when  they  were accidentally  exposed  to  unknown
concentrations  of HEX. The HEX escaped into the room when
an aerated exposure chamber was opened.

    In  a 48-block area  surrounding a contaminated  sewer
line  in  Kentucky, USA,  questionnaires  were sent  to  a
selected  sample of residents.   A total of  212 occupants
were  surveyed.  Only 3.8%  of the residents  reported  an
unusual odour. The most common symptoms were stomach aches
(5.2%),  burning  or  watery eyes  (4.7%),  and  headaches
(4.7%).  There was no association between the frequency of
symptoms  and the distance of houses from the contaminated
sewer  line.  No significant ambient air concentrations of
HEX were found in these areas (Kominsky et al., 1978).

9.2.  Occupational exposure

    The  US National Institute for Occupational Safety and
Health  (NIOSH, 1980) stated that  1427 workers were occu-
pationally  exposed to HEX.   Officials from the  Velsicol
Chemical Corporation estimated that 157 employees had been
potentially  exposed to HEX  in their production  and pro-
cessing facilities.

    A  well-documented incident of acute human exposure to
HEX occurred in March 1977 at the Morris Forman Wastewater
Treatment  Plant in Louisville,  Kentucky, USA (Wilson  et
al., 1978; Morse et al., 1979; Kominsky et al., 1980). The
details of the incident are included in the original NIOSH
Hazard  Evaluation and Technical Assistance  Report Number
TA-77-39  (Kominsky et al., 1978), which is available from
the US National Technical Information Service (NTIS). This

a   Memorandum from G. Leonardos to P. Levins on Hooker
    special priority samples (odour properties).

treatment  facility was contaminated with  approximately 6
tonnes  of HEX and octachlorocyclopentene, a waste product
of HEX manufacture (Morse et al., 1979). The contamination
was traced to an illegal dumping in one large  sewer  line
that  passed  through  several  populated  areas.  Concen-
trations of HEX detected in the sewage at the  plant  were
as  high as 1000 mg/litre,  and levels in  the sewer  line
were  up to 100 mg/litre. Air samples taken from the sewer
line  showed  HEX  concentrations to  be  as  high as  4.5
mg/m3 (400 ppb).   Although the airborne concentrations of
HEX  at the time of the exposure in the treatment facility
were  not  known,  airborne concentrations  in the primary
treatment  areas (screen and grit chambers) ranged between
3.05  and 10.96 mg/m3   (270 and 970 ppb) 4 days after the
plant  had  closed.  It should  be  noted  that the  ACGIH
8 h-TWA for HEX was 0.1 mg/m3   (10 ppb) in 1977.  Workers
tried to remove an odoriferous and sticky  substance  from
the  bar screens and grit collection system by using steam
during  clean-up of the contamination. This procedure pro-
duced  a blue haze  which permeated the  primary treatment
area.  The airborne HEX concentration of the blue haze was
reported to be 217 µg/m3 (19.2 ppm) (Kominsky et al., 1980).

    The  US Centers for  Disease Control (CDC)  and  NIOSH
sent  representatives  to  the plant  with  questionnaires
about  the type and  duration of symptoms  (Morse et  al.,
1979;  Kominsky et al., 1980).  In all, 193 employees were
identified  as having been  potentially exposed for  2  or
more days during the 2 weeks before the plant  was  closed
(Morse  et al., 1979).  The questionnaire was sent to each
of these 193 workers and 145 (75%) responded. Workers with
complaints  of  mucous  membrane irritation  were  given a
physical  examination,  and  blood and  urine samples were
collected for clinical screening by an independent labora-
tory.  Data were also collected on the exposure levels and
symptoms  experienced  by  several  people  who  had  been
acutely exposed to the chemical vapours.

    The results of the CDC and NIOSH questionnaires showed
that  the  odour of  HEX had been  detected by 94%  of the
workers  before the onset  of symptoms.  The  most  common
symptoms  reported  were  eye irritation  (59%), headaches
(45%),  and throat irritation (27%) (Table 18).  Of the 41
plant  workers  examined, six  had  physical signs  of eye
irritation  (i.e.  lacrimation  or redness)  and  five had
signs  of skin irritation.   Laboratory analyses of  blood
and  urine  specimens  from these  workers showed marginal
increases in lactic dehydrogenase activity in 27% of cases
and proteinuria in 15%. Three weeks later,  no  abnormali-
ties were detected in the blood and urine tests. After six
weeks, some of the clinical symptoms persisted  in  25-45%
of the employees (Morse et al., 1978).

Table 18.  Symptoms of 145 waste-water treatment 
plant employees exposed to HEX (Louisville, 
Kentucky, USA, March 1977)a
Symptom                No. of         Percent of 
                       employees      employees
                       with symptoms  with symptoms
Eye irritation         86             59
Headache               65             45
Throat irritation      39             27
Nausea                 31             21
Skin irritation        29             20
Cough                  28             19
Chest pain             28             19
Difficult breathing    23             16
Nervousness            21             14
Abdominal cramps       17             12
Decreased appetite     13             9
Decreased memory       6              4
Increased saliva       6              4
a   From: Morse et al. (1978).

    Although  there was difficulty in  measuring the level
of exposure received by the plant workers, more  than  50%
of  the  clean-up  crew were  monitored.  Laboratory tests
showed  no  significant  abnormalities in  renal  function
tests,  complete blood counts, or  urinalysis, but several
minimal or mild abnormalities were found in liver function
tests (Kominsky et al., 1980). The abnormalities in 18 out
of  97 clean-up  workers  are listed  in  Table 19.  These
people  also had physical  signs of mucous  membrane irri-
tation. A more detailed correlation between acute exposure
level data and symptomatology was reported for nine adults
(Kominsky et al., 1980).  The data appear in Table 20. The
exposure  levels could not be estimated accurately because
of prior exposure or because the worker had  used  protec-
tive equipment.

Table 19.  Abnormalities detected in clean-up 
workers at the Morris Forman treatment plant, 
Louisville, Kentucky, USAa
Laboratory test   Normal range   Abnormal results
                                 Range     No.b
Serum glutamate
oxaloacetate      7-40 mU/ml     40-49     5
transaminase                     50-59     1
                                 60-69     4
                                 70-79     0
                                 80-89     1
                                 90-99     1

Serum alkaline    30-100 mU/ml   100-109   3
phosphatase                      110-119   1
                                 120-129   1

Serum total       0.15-10 mg/dl  1.0-1.9   1c

Serum lactate     100-225 mU/ml  230-239   1
a   From: Kominsky et al. (1980).
b   For individuals with more than one serial 
    blood test, only the most abnormal result is 
c   Associated with a serum glutamate oxaloacetate 
    transaminase activity of 66 mU/ml.

Table 20.  Individual exposure symptomatology correlations at the Morris Forman treatment plant (Louisville, Kentucky, USA)a
No. of    Estimated airborne          Immediate symptoms                      Persistence of symptoms              Laboratory 
workers   exposureb                                                                                                results
1         19.2 ppm HEX and 650 ppb    lacrimation; skin irritation on face    1.5 h post-exposure: fatigue;        normal results 
          OCCP for several seconds    and neck; dyspnoea and chest            erythema of exposed skin; eye        4 days
          (no protective equipment)   discomfort;nausea (several min later)   irritation subsided in 1 day;        post-exposurec
                                                                              chest discomfort persisted
                                                                              several days

3         7083 ppb HEX and 446 ppb    lacrimation; irritation of exposed      asymptomatic at 2 h, except          normal results 
          OCCP for several seconds    skin                                    for soreness around eyes             7 days post-
          (half-face respirator)                                                                                   exposure in 
                                                                                                                   one workerc

2         40-52 ppb HEX and           slight eye irritation                   no symptoms after cessation of       normal results 
          9-21 ppb OCCP                                                       exposure                             7 days post-
          (half-face respirator)                                                                                   exposure in one

2         exact exposure unknown      slight skin irritation                  faces felt "puffy" and "windburned"  none available
          (half-face respirator)                                              for 1-2 days after exposure; this 
                                                                              was noted also by friends and 
                                                                              family; no residual skin lesions.

1         980 ppb HEX for 15 min;     irritated eyes; nasal irritation        eyes felt "dry and irritated" for    none available
          OCCP not measured           and sinus congestion after 2 weeks      2-3 days after exposure; nasal
          (no protective equipment)   of intermittent exposures               irritation ceased within 1-2 days
                                                                              of cessation of exposure.
a   From: Kominsky et al. (1980).
b   OCCP = Octachlorocyclopentene.
c   Laboratory work was same as carried out on clean-up crew.
    Hazards to workers in treatment plants can result from
chemical  compounds  contained  in  the  industrial  waste
treated  in municipal waste-water plants. The HEX-contain-
ing wastes from a pesticide manufacturer were treated in a
municipal   waste-water   treatment   plant  at   Memphis,
Tennessee,  USA.   In  1978,  the  workers  at  this plant
reported  symptoms similar to those reported by workers in
the Louisville plant referred to above. The air and waste-
water  were monitored, and  analyses of urine  and  blood,
liver  function tests, and illness  symptom questionnaires
were  completed.  Workers  from  another  waste  treatment
plant, where no pesticide wastes had been  received,  were
used  as a control  group.  No statistical  differences in
urine  HEX concentrations or liver  function tests between
the  exposed  and  control  groups  were  found,  although
differences   in  levels  of  HEX-related  compounds  (co-
contaminants) were detected (Elia et al., 1983).

9.3.  Epidemiological studies

    Mortality  studies  have  been carried  out on workers
involved  in the production of  HEX or formulation of  HEX
products.   Shindell et al. (1980) studied a cohort of 783
current  and former workers who  had been employed at  the
Velsicol Chemical Corporation plant at Marshall, Illinois,
between  1946 and 1979.  The  purpose of the study  was to
evaluate  the overall health  status of all  employees who
had been present during the manufacture of chlordane for 3
months  or more.  There were no significant differences in
mortality  rates between these  employees and the  overall
USA  population.  The observed  value for deaths  from all
causes,  including heart disease and cancer, was less than
the expected value in the overall USA population.

    Shindell et al. (1981) completed another epidemiologi-
cal  study for the  Velsicol Chemical Corporation  at  its
Memphis,  Tennessee, plant covering the  period 1952-1979.
This  coincided  with  the manufacture  of  heptachlor,  a
pesticide  made  from  HEX.  The  reseachers  studied 1115
current and former employees who had worked  for  3 months
or  more.  Again, there  was no significant  difference in
mortality between the control and exposure groups.

    Concomitant  with the study  performed by Shindell  et
al.  (1980), Wang & MacMahon (1979) conducted a retrospec-
tive mortality study of workers employed at  the  Marshall
and  Memphis plants, where  chlordane and heptachlor  were
manufactured  between  1946  and 1976.  They  studied 1403
males who had worked at the plants for more than 3 months.
There  were 113 observed deaths compared with 157 expected
deaths, giving a standardized mortality ratio (SMR) of 72.
Among  the various causes of  death, the two highest  SMRs
were  134  for lung  cancer  and 183  for  cerebrovascular
disease, but only the latter figure was statistically sig-
nificant  (P < 0.05). The excess mortality due to cerebro-
vascular  disease  was  not  related  to  the  duration of

exposure or to the latency period, and occurred only after
termination   of  employment.  Shindell  &  Ulrich  (1986)
updated their 1980 data set with additional  worker  data.
There was no information specific to HEX exposure.

    Buncher et al. (1980) studied the mortality of workers
at  a chemical plant that produced HEX.  They examined 341
workers  (287 male  and  54 female), together  with  their
health records, who had worked at the plant for  at  least
90 days between 1 October 1953 and 31 December 1974. Their
vital  status was determined  through 1978.  The  expected
numbers  of  deaths,  based  on  the  USA  population  and
specific for sex, age, and calendar year, were calculated.
The  SMR for all causes of death was 69.  Deaths caused by
specific  cancers, all cancers, and diseases of the circu-
latory   and  digestive  systems  were   also  fewer  than
expected. The authors noted that the time that had elapsed
since  the initial exposure (25 years at most) reduced the
power  of the  study to  detect cancers  that may  have  a
10-40 year latent period.

    Similar  studies have been  performed on a  cohort  of
workers in the Shell International Petroleum plants in the
Netherlands.  These reports have been reviewed extensively
in  Environmental Health Criteria 91:  Aldrin and Dieldrin
(WHO, 1989).


10.1.  Evaluation of human health risks

    The general population is not at risk from exposure to
HEX. However, people living near HEX processing  and  pro-
duction  facilities, as well  as handlers of  the chemical
and  its  waste, are  at risk. Exposure  to HEX can  occur
through  several  different  routes. However,  HEX is much
more  toxic when inhaled  than when ingested  or following
dermal contact.  Skin exposure studies have shown that HEX
can  cause irritation, together with visceral changes that
are similar to those that result from oral administration.
Inhalation studies in animals have shown that  HEX  vapour
is  very irritating, repeated exposure  to 1.13-2.26 mg/m3
(0.1-0.2 ppm)   causing  pulmonary  pathological  changes.
Acute  toxic symptoms, including headaches, nausea, dizzi-
ness, and respiratory distress, have been reported.  Based
on a 90-day inhalation study in mice and rats, a  NOEL  of
0.45 mg/m3   (0.04 ppm) has been estimated. No information
is available on the long-term effects of a single exposure
or of continuous exposure to HEX.

    A  carcinogenic study of  HEX has been  completed (but
not  evaluated) by the US  National Toxicology Program.  In
 vitro mutagenicity and cell transformation  tests yielded
negative  results, as did an  in vivo mouse dominant lethal
assay  at the  levels tested.   There was  no evidence  of
teratogenicity  in  oral  exposure studies  in which three
species were examined.

    The toxic effects of HEX exposure on the human respir-
atory system are of major concern.  Although the long-term
toxicity data are limited, systemic toxic effects  of  HEX
inhalation  have been observed after  short-term exposure,
suggesting  that long-term inhalation exposure to low con-
centrations  of  HEX  could cause  adverse health effects.
Limited  epidemiological studies of workers exposed to HEX
at  levels  above those  known  to induce  adverse  health
effects have been conducted, although concomitant exposure
to  other  chemicals was  known  to have  occurred.  These
workers  complained of headaches, eye and skin irritation,
nausea,   dizziness,  and  respiratory  distress,  as  did
individuals  living  near  areas  where  there  were   HEX

10.2.  Evaluation of effects on the environment

    Release  of HEX into  the environment can  result from
the  production, processing and  use of HEX,  disposal  of
waste  containing HEX or  from products contaminated  with
HEX.  Only a small proportion of the total amount  of  HEX
released into the environment from production, processing,
and  use  can be  expected to persist  beyond a few  days.
However,  waste disposal has resulted in HEX persisting in

soil, sediment, and ground water. There is little monitor-
ing  information on the levels  of HEX in air,  water, and
sediment.   The  exposure  of  organisms  in  the  aquatic
environment to HEX is therefore difficult to quantify.

    HEX  may undergo photolysis, hydrolysis, and biodegra-
dation.  In water, photolysis is the dominant  process  in
direct  sunlight, hydrolysis being the next most important
degradation route. Volatilization to the atmosphere occurs
from both water and soil.  Biodegradation occurs  in  soil
under  both aerobic and anaerobic conditions and in sewage
sludge.   In water and aquatic sediment, biodegradation is
initially limited. Information on the adaptation of micro-
organisms to degrade HEX is limited.  HEX has a calculated
tropospheric residence time of approximately 5 h.

    Laboratory  studies  suggest  that HEX  is  relatively
immobile in soil, particularly in soil with a high organic
content.  However, leaching and  movement in ground  water
has been reported in field studies.

    HEX  has been shown to  be toxic to aquatic  life at a
level of 1-100 µg/litre.   However, little information has
been  obtained under field conditions  (long-term exposure
at  low concentration in  the presence of  sediment).  The
actual  hazard to aquatic life is, therefore, difficult to
assess.  HEX is toxic to aquatic microorganisms  but  less
toxic  to  soil  microorganisms.  Exposure  of terrestrial
organisms,  except  at or  near  disposal sites,  would be
expected to be low.


11.1.  Conclusions

*   The general population is not at risk  from  exposure
    to  HEX, except in the  case of people residing  near
    contaminated areas.

*   The long-term human health effects of continuous low-
    level exposure are not known. Handlers of the product
    and  its waste,  as well  as sewage  workers, are  at

*   Results  of  laboratory  studies  indicate  that  HEX
    should  be  degraded  rapidly in  the  environment by
    photolysis,  hydrolysis, or biodegradation. The rela-
    tive  importance of these  processes varies with  the
    medium.  HEX is not  a widespread environmental  con-
    taminant  and the available  data suggest that  it is
    only found associated with production, processing and
    disposal sites.  HEX does not bioaccumulate.

*   Acute  laboratory tests show that HEX is highly toxic
    to  aquatic microorganisms, invertebrates,  and fish,
    but  less  toxic  to soil  microorganisms.   However,
    information  obtained under environmentally realistic
    conditions  is limited.  The potential  hazard to the
    general environment is expected to be low.

11.2.  Recommendations for protection of human health and
the environment

*   Occupational  exposure to HEX should  be minimized by
    the  use of closed  systems. Guidelines for  the dis-
    posal of HEX and HEX wastes should be followed.

*   Environmental  monitoring  is  needed to  examine the
    persistence  and fate of HEX  in all media near  pro-
    duction,  processing  and  disposal sites,  and  also
    hazardous  waste  incinerators.  Monitoring  data are
    required  for HEX in drinking-water,  and in surface,
    shower, and ground water.


*   Biomarker  technology should be developed  to indicate
    the  possibility of past  or current actions  of  HEX.
    Such  biomarkers  could be  stable metabolites derived
    from  HEX and its impurities  that are present in  the
    original preparation.

*   Research  is needed on the metabolic, degradative, and
    reactive  products to understand  the fate of  HEX  in
    human beings and the environment.

*   Further study of the apparent disparity between degra-
    dation  under laboratory conditions and  that observed
    in the environment is needed.

*   The  efficacy and safety  of current disposal  methods
    should  be  evaluated  and their  present  and  future
    health impacts assessed.

*   Developmental  and reproductive studies of HEX need to
    be conducted, with emphasis on the inhalation route of

*   Methods for the early warning of the presence  of  low
    levels of HEX should be developed.


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PODOWSKI, A.A. & KHAN, M.A.Q. (1979) Fate of hexachlorocyclopentadiene in
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PODOWSKI, A.A. & KHAN, M.A.Q. (1984) Fate of hexachlorocyclopentadiene in
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RAND, G.M.,  NEES, P.O.,  CALO, C.J.,  ALEXANDER,  D.J.,  &  CLARK,  G.C.
(1982a) Effects  of inhalation  exposure to  hexachlorocyclopentadiene on
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RIECK, C.E.  (1977a) Effect  of hexachlorocyclopentadiene on soil microbe
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Department   (Unpublished   report   prepared   for   Velsicol   Chemical
Corporation, Chicago).

RIECK, C.E.  (1977b) Soil  metabolism  of  14C-hexachlorocyclopentadiene,
Lexington,  Kentucky,   University  of   Kentucky,  Agronomy   Department
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RIECK, C.E.  (1977c) Volatile  products of 14C-hexachlorocyclopentadiene,
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employees of  Velsicol Chemical  Corporation plant,  Marshall,  Illinois,
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SHINDELL &  ASSOCIATES (1981)  Report of  the epidemiologic  study of the
employees of  Velsicol Chemical  Corporation plant,  Memphis,  Tennessee,
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SINHASENI,  P.,   D'ALECY,  L.G.,  HARTUNG,  R.,  &  SHLATER,  M.  (1982)
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SINHASENI,  P.,   D'ALECY,  L.G.,  HARTUNG,  R.,  &  SHLATER,  M.  (1983)
Respiratory effects  of hexachlorocyclopentadiene on intact rainbow trout
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SPEHAR, R.L.,  VEITH, G.D., DEFOE, D.L., & BERGSTEDT, B.A. (1977) A rapid
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SPEHAR, R.L., VEITH, G.D., DEFOE, D.L., & BERGSTEDT, B.A. (1979) Toxicity
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7: 87-100.


    Information  on guidelines, recommendations, and stan-
dards used in various countries is given in Table 21.

Table 21.  Guidelines, recommendations and standards used in various countries/areasa
Country       Type             Medium/situation   Exposure limit description    Valueb         Date
                                                  or remark
Australia     recommendation   air/occupational   threshold limit value/time-   0.1 (0.01)     1983                 
                                                  weighted average                                                    
                                                  short-term exposure limit     0.3 (0.03)                          
Belgium       recommendation   air/occupational   threshold limit value/time-   0.1 (0.01)     1988                 
                                                  weighted average                                                    
Canada        regulation       air/occupational   threshold limit value/time-   0.1 (0.01)     1980                 
                                                  weighted average                                                    
Canada        regulation       transport          specific transportation                      1987                 
Finland       recommendation   air/occupational   time-weighted average         1.0 (0.1)      1989                 
                               skin               short-term exposure limit     3 (0.3)        1989                 
Netherlands   recommendation   air/occupational   time-weighted average/        0.11 (0.01)    1986                 
Federal       regulation       waste              "toxic waste" subject to                     1981                 
 Republic                                         specific handling,                                                  
 of Germany                                       transport, treatment,                                               
                                                  storage, and disposal                                               
Switzerland   regulation       air/occupational   time-weighted average         0.1 (0.01)     1987                 
USA           regulation       water              ambient                       1 µg/litre     1980                 
                                                  water quality criteria                                              

Table 21 (contd.)
Country       Type             Medium/situation   Exposure limit description    Valueb         Date
                                                  or remark
USA (ACGIH)   recommendation   air/occupational   time-weighted average         0.1 (0.01)     1980                 
USA           regulation       air/occupational   time-weighted average         0.1 (0.01)     1989                 
USA           regulation       water/land         notification of spill                        1983                 
                                                  of 0.45 kg (1 lb)                                                   
                                                  in 24-h period                                                      
USA           regulation       waste transport    "toxic waste" subject to                     1980                 
                                                  specific handling,                                                  
                                                  transport, treatment,                                               
                                                  storage and disposal                                                
USA           draft            drinking-water     lifetime                      7 µg/kg        1990                 
              recommendation                                                    per day                             
USSR          regulation       air/occupational   threshold limit value         0.01 (0.001)   1989                 
USSR          regulation       water              maximum allowable             1 mg/litre     1985                 
USSR          regulation       air/ambient        short-term exposure limit     0.001          1987                 
Yugoslavia    regulation       air/occupational   time-weighted average         0.1            1985                 
a   From: IRPTC (1989)
b   Unless stated otherwise, units are mg/m3. The value in parts per million is given in parentheses.


    L'hexachlorocyclopentadiène (HEX) est un liquide dense
et  ininflammable, de couleur jaune pâle à jaune verdâtre,
et qui possède une odeur piquante caractéristique.  Le HEX
est très réactif; il donne lieu à des réactions d'addition
et de substitution et à des réactions de Diels-Alder.

    Aux  Etats-Unis d'Amérique, la Velsicol  Chemical Cor-
poration est actuellement le seul producteur de  HEX.   En
Europe,  il est produit aux Pays-Bas par la Société Shell.
Les  chiffres  de  production sont  confidentiels  mais on
estime  que  3600  à  6800 tonnes  de  HEX  sont produites
actuellement  aux  Etats-Unis.   En  1988,  la  production
mondiale  était  d'environ 15 000 tonnes  (BUA, 1988).  Le
HEX  est utilisé comme intermédiaire dans la production de
nombreux  pesticides,  mais  quelques pays  en  ont limité
l'emploi  à la fabrication de  certains pesticides organo-
chlorés.   Il est également utilisé pour la fabrication de
retardateurs de flamme, de résines et de colorants.

    Au cours de la production et de la  transformation  du
HEX,  de petites quantités sont libérées dans l'environne-
ment.  Ce peut être  également le cas  lorsqu'il constitue
une  impureté de certains  des produits pour  lesquels  il
sert  d'intermédiaire.  La libération de HEX peut interve-
nir  pendant ou  après le  rejet.  On  ne dispose  que  de
données limitées sur la surveillance des concentrations de
cette substance dans l'environnement. D'après ces données,
il  semble que le HEX soit présent essentiellement dans le
compartiment  aquatique et y soit associé aux sédiments et
aux  matières organiques, sauf  là où il  y a eu  rejet ou
libération du produit.  D'après les études en laboratoire,
il  y a sorption du  HEX par la plupart  des particules du
sol.   Toutefois, on a  fait état d'un  lessivage et  d'un
mouvement dans les eaux souterraines.

    Aux Etats-Unis d'Amérique, on estime que 5,9 tonnes de
HEX  sont libérées annuellement  dans le milieu  (US  EPA,
1989).   En République fédérale  d'Allemagne et aux  Pays-
Bas,  environ  400 à  500 kg de HEX  ont été libérés  dans
l'atmosphère en 1987 (BUA, 1988). En raison des propriétés
physiques  et chimiques du  HEX, il ne  devrait  subsister
qu'une faible fraction de ces émissions.

    En  s'appuyant sur les données de laboratoire disponi-
bles,  on a modélisé  la destinée et  le transport du  HEX
dans  l'atmosphère et calculé que son temps de séjour dans
la troposphère était d'environ 5 h.  On a fait  état  d'un
transport  atmosphérique  de HEX  à  partir d'une  zone de
stockage  de déchets et de puits au cours du traitement de
rejets industriels.

    Dans  l'eau,  le HEX  peut  subir une  photolyse,  une
hydrolyse  et  une  biodégradation.   Dans  les  eaux  peu
profondes  son temps de demi-photolyse est inférieur à une
heure.  Dans les eaux plus profondes où la  photolyse  est
exclue,  le  temps  de demi-hydrolyse  varie  de plusieurs
jours à environ trois mois et la biodégradation est encore
beaucoup plus lente.  Le HEX se volatilise à la surface de
l'eau  à  une vitesse  qui dépend de  la turbulence et  du
degré de sorption par les sédiments.

    En raison de sa faible solubilité dans l'eau,  le  HEX
devrait être relativement immobile dans le sol.  Toutefois
on  en a trouvé dans  des eaux souterraines. La  volatili-
sation  de cette substance qui se produit très vraisembla-
blement à la surface du sol est d'autant  plus  importante
que  la teneur  du sol  en matières  organiques  est  plus
faible.   Les résultats d'études en  laboratoire indiquent
que l'hydrolyse chimique et la métabolisation microbienne,
qu'elles soient aérobie ou anaérobie, devraient réduire la
teneur des sols en HEX.

    En principe, le HEX devrait avoir un pouvoir  de  bio-
amplification  notable en raison de sa forte lipophilicité
(log  du  coefficient  de partage  octanol/eau). Toutefois
les  données expérimentales ne corroborent pas cette hypo-
thèse.  Des études sur animaux d'expérience ont montré que
le  14C-HEX   est à la fois métabolisé et excrété dans les
quelques  heures  qui  suivent l'administration  par  voie
orale,  la rétention dans  l'organisme étant très  faible.
Le  facteur de bioconcentration à  l'état stationnaire est
inférieur  à 30 chez les  poissons.  Les facteurs de  bio-
accumulation  calculés à partir de modèles d'écosystèmes à
court  terme indiquent que le potentiel d'accumulation est
modéré. Il semblerait donc que le HEX et  ses  métabolites
ne  persistent  pas et  ne  s'accumulent pas  en quantités
importantes dans les systèmes biologiques.

    On  a montré qu'à faibles concentrations, le HEX était
toxique pour la faune aquatique.  Des cas de mortalité par
intoxication  aiguë  (exposition de  48  à 96 h)  ont  été
observés  chez des crustacés et des poissons dulçaquicoles
et  marins  à  des  concentrations  nominales  de   32   à
180 µg/litre,    dans  des  systèmes statiques  dont l'eau
n'était pas renouvelée au cours de l'épreuve.  Etant donné
que  le temps de demi-photolyse est inférieur à une heure,
la concentration en HEX devrait avoir diminué  de  manière
importante  au cours de  la période d'exposition  utilisée
dans ces études.  Les seules études au cours desquelles on
a  mesuré les concentrations de HEX dans de l'eau courante
ont  donné une valeur  de la CL50   à 96 h de   7 µg/litre
pour  le vairon  américain et  une crevette  de mer.   Les
épreuves  effectuées  sur  ces  deux  espèces  ont  donné,
respectivement pour la CL10   et la CL40,   des valeurs de
3,7 et de 0,7 µg/litre.

    Des  épreuves statiques de  sept jours effectuées  sur
des  algues marines à des  concentrations nominales allant
de 3,5 à 100 µg/litre   ont fait ressortir  une  réduction
moyenne de la croissance (CE50),   qui était  fonction  de
l'espèce.   En milieu aqueux, le  HEX est toxique pour  de
nombreux microorganismes à des concentrations nominales de
0,2 à 10 mg/litre, c'est-à-dire à des valeurs sensiblement
plus importantes que celles qui sont nécessaires pour tuer
la  plupart des animaux et des plantes aquatiques.  Le HEX
semble  être moins toxique pour les microorganismes terri-
coles  que pour les microorganismes  aquatiques, probable-
ment  en raison  de l'adsorption  du HEX  sur  la  matrice
constituée par le sol.

    On pense que l'exposition devrait être faible mais les
données  actuellement disponibles sont  insuffisantes pour
permettre  de déterminer les effets de l'exposition au HEX
sur la flore et la faune terrestres.

    La  résorption du HEX non modifié est minimale du fait
de  sa réactivité vis-à-vis des membranes et des tissus de
l'organisme et plus particulièrement, du contenu des voies
digestives.  Après administration par voie orale, percuta-
née  ou  par  inhalation,  la  majeure partie  du  14C-HEX
radiomarqué est retenue au niveau des reins, du  foie,  de
la trachée et des poumons des animaux  d'expérience.   Une
fois résorbé, le HEX est métabolisé et rapidement excrété,
principalement  dans  les urines,  un  peu moins  dans les
matières  fécales et à raison  de moins de 1%,  dans l'air
expiré.   La durée nécessaire pour  l'élimination complète
est  d'environ  30 h quelle  que  soit la  voie d'adminis-
tration.   Après  inhalation  ou administration  par  voie
intraveineuse,  le composé parent ne se retrouve plus dans
les  excréta; on a  isolé des métabolites  fécaux et  uri-
naires mais ils n'ont pas été identifiés. C'est d'ailleurs
la  raison pour laquelle il est très difficile de se faire
une  idée de la pharmacocinétique du HEX et d'élucider son
mode d'action.

    La  CL50   par inhalation  (sur une période  d'environ
4 h)  est de 17,9 mg/m3   chez  le rat mâle et  de 39,1 mg
par  m3    chez  la  ratte.   Bien  qu'il  existe quelques
différences  d'une espèce à  l'autre, notamment entre  les
cobayes, les rats, les lapins et les souris,  les  vapeurs
de HEX sont extrêmement toxiques pour toutes  les  espèces
étudiées.   C'est par inhalation  qu'il se révèle  le plus
toxique,  par  comparaison avec  l'administration orale ou
percutanée,  et il se  montre également extrêmement  irri-
tant.   Quelle  que  soit la  voie d'administration, toute
exposition  aiguë entraîne des effets  généraux pathologi-
ques  au  niveau des  poumons, du foie,  des reins et  des

    L'administration  de  HEX par  voie  orale à  des rats
(30 mg/kg  et par jour) et  à des souris (75 mg/kg  et par
jour)  pendant  91 jours  a déterminé  une  néphrose ainsi
qu'une   inflammation  et  une  hyperplasie  de  l'estomac
antérieur.  On n'a pas relevé de signes  manifestes  après
exposition  de  souris ou  de rats à  qui l'on avait  fait
inhaler  du HEX à  raison de 2,26 mg/m3    (0,2 ppm),  six
heures  par  jour,  cinq  jours  par  semaine  pendant  14
semaines.   A la concentration de 1,69 mg/m3   (0,15 ppm),
on  a observé seulement  une petite irritation.   Des rats
exposés  de la même  manière à 5,65 mg/m3    (0,5 ppm)  de
HEX  pendant  30 semaines  ont présenté  des modifications
histopathologiques  au  niveau  du foie,  des voies respi-
ratoires  et des  reins.  Une  autre étude  du même  genre
portant  sur des rats et des souris et qui s'est prolongée
pendant  90 jours  a  révélé des  effets  respiratoires  à
partir  de 4,52 mg/m3   (0,4 ppm).   Le HEX ne  s'est  pas
révélé  mutagène lors d'épreuves  in vitro, qu'il  y ait ou
non  activation  métabolique.   Il s'est  également révélé
inactif  dans  les épreuves  de  dominance létale  chez la
souris.   Administré par voie  orale à des  rats et à  des
souris,  il ne  s'est pas  révélé tératogène,  mais on  ne
dispose  d'aucune  donnée  relative  à  sa  tératogénicité
éventuelle  après exposition par voie respiratoire.  On ne
dispose  que de données limitées  sur l'exposition humaine
au  HEX  et sur  ses effets.  On  a observé des  incidents
isolés  au cours desquels il  y a eu forte  irritation des
yeux, du nez, de la gorge et des poumons. Cette irritation
était   généralement  brève,  les  victimes  commençant  à
récupérer  dès cessation de l'exposition.  Après une expo-
sition  de  courte durée  on  n'a noté  aucune  différence
statistiquement  significative  au  niveau  de   certaines
enzymes  hépatiques  entre  les  groupes  exposés  et  les
groupes  témoins.  On ignore quels peuvent être les effets
à  longue échéance sur  la santé humaine  d'une exposition
continue  à  de faibles  concentrations  de HEX  ou  d'une
exposition intermittente à des fortes concentrations.  Les
personnes  qui sont amenées à manipuler cette substance ou
des déchets qui en contiennent, ainsi que  les  égoutiers,
travailleurs  des  usines  de traitement  d'eaux  usées et
personnes  qui  résident  à proximité  de décharges, pour-
raient  être exposés au risque du fait des possibilités de
contact  avec  cette substance  ou  avec les  déchets  qui
résultent de sa fabrication.

    La  base de données dont  on dispose n'est pas  suffi-
sante pour qu'on puisse évaluer la cancérogénicité du HEX.
Le Programme toxicologique national des Etats-Unis (NTP) a
procédé  à des  études d'inhalation  sur des  rats et  des
souris pendant toute la durée de leur vie.  Une fois qu'un
rapport  sur la pathologie  observée aura été  publié,  on
aura  une meilleure idée des effets à long terme éventuels
de  l'exposition au HEX.  En  ce qui concerne la  cancéro-
génicité de cette substance, il faudra différer  les  tra-
vaux  dans l'attente des résultats des épreuves effectuées

par le NTP.  Le Centre international de recherche  sur  le
cancer  a examiné les données existantes sur le HEX et l'a
classé  dans  le Groupe 3  (ce  qui indique  qu'en  raison
d'insuffisances quantitatives ou qualitatives importantes,
il n'est pas possible de déterminer, au vu  des  résultats
disponibles,  s'il  y  a  présence  ou  absence   d'effets
cancérogènes). Un certain nombre d'études épidémiologiques
sont  citées dans la  littérature;  on n'a  pas fait  état
d'une   incidence  accrue  de  cancers,   de  localisation
quelconque,  qui puisse  être attribuée  au HEX  ou à  ses


    El  hexaclorociclopentadieno (HEX) es un líquido denso
de  color amarillo pálido o verdoso, no inflamable, con un
olor acre característico. Su masa molecular relativa es de
272,77 y  es poco soluble en agua.  El HEX es muy reactivo
y  experimenta  reacciones  de adición,  sustitución  y de

    En  los EE.UU., la Velsicol Chemical Corporation es la
única empresa que actualmente produce HEX.  En  Europa  lo
fabrica la Shell Chemical Corporation en los Países Bajos.
Los  datos de producción  son propiedad de  las  empresas,
pero se calcula que al año se producen en los EE.UU. entre
3600  y  6800 toneladas de  HEX.  En 1988,  la  producción
mundial  fue  de  aproximadamente 15 000  toneladas  (BUA,
1988).   Aunque el HEX  se utiliza como  intermedio en  la
producción  de  numerosos plaguicidas,  algunos países han
restringido su empleo en la fabricación de ciertos plagui-
cidas  organoclorados. También se utiliza en la producción
de pirorretardantes, resinas y tintes.

    Durante  la  fabricación  y elaboración  del  HEX,  se
liberan  pequeñas  cantidades  de la  sustancia  al  medio
ambiente.  También puede liberarse cuando aparece en forma
de impureza en algunos de los productos para los que sirve
de  intermedio.  El HEX puede liberarse tanto durante como
después de su evacuación. Sólo se dispone de  datos  limi-
tados  de vigilancia de  los niveles ambientales  de  HEX.
Esos  datos  indican  que  aparece  principalmente  en  el
compartimento  acuático y que se asocia a los sedimentos y
la  materia orgánica del fondo salvo en los lugares en los
que se ha producido evacuación o liberación. En el labora-
torio,  el HEX se adsorbe  sin dificultad a la  mayoría de
los  tipos de partículas del  suelo.  Sin embargo, se  han
comunicado casos de lixiviación y de movimiento  en  aguas

    En los EE.UU., se calcula que la liberación  total  de
HEX  al medio ambiente en  un año es de  5,9 toneladas (US
EPA,  1989).  En la  República Federal de  Alemania y  los
Países Bajos, se emitieron en 1987 alrededor de 400-500 kg
(BUA, 1988).  Dadas las características físicas y químicas
del  HEX, es  de esperar  que solo  persista  una  pequeña
fracción de esas emisiones.

    Basandose  en los datos de laboratorio disponibles, se
ha  formulado un modelo sobre  el destino y el  transporte
del  HEX en la  atmósfera y se  ha calculado que  tiene un
tiempo  de  residencia  de aproximadamente  5 horas  en la
troposfera.   Se ha comunicado la existencia de transporte
atmosférico de HEX desde una zona en la que  se  almacenan
desechos  y a partir  de las cisternas  durante el  trata-
miento de desechos industriales.

    En  el  agua,  el HEX  puede  experimentar  fotolisis,
hidrólisis  y  biodegradación.   En aguas  poco profundas,
tiene  una  semivida fotolítica  de  < 1 h.  En  aguas más
profundas,  donde  la  fotolisis  se  ve  impedida,  se ha
observado  que la semivida hidrolítica  puede variar entre
varios  días y aproximadamente tres meses, mientras que es
de  prever  que  la  biodegradación  se  produzca  con más
lentitud.  Se sabe que el HEX se volatiliza en  las  aguas
superficiales, y que la tasa de volatilización  varia  con
la turbulencia y con la adsorción a los sedimentos.

    Debido a su baja solubilidad en el agua, el  HEX  debe
ser relativamente inmóvil en el suelo.  Sin embargo, se ha
detectado la sustancia en aguas subterráneas. La volatili-
zación, que tiene más probabilidades de producirse  en  la
superficie  del  suelo,  guarda relación  inversa  con los
niveles  de materia orgánica  en éste.  Los  resultados de
estudios  en laboratorio indican que la hidrólisis química
y  el metabolismo microbiano, tanto  aeróbico como anaeró-
bico, deben reducir los niveles de HEX en los suelos.

    En  teoría, el potencial  de biomagnificación del  HEX
debe  ser importante debido  a su elevada  lipofilia  (log
coeficiente de partición octanol/agua).  Este extremo, sin
embargo,  no ha sido demostrado en pruebas experimentales.
Los estudios en animales de laboratorio han demostrado que
el  14C-HEX   es metabolizado  y excretado durante  de las
primeras horas que siguen la administración de  una  dosis
por vía oral, y que la proporción que queda retenida en el
organismo  es  pequeña.  En  los  peces, los  factores  de
bioconcentración en estado estable son < 30.  Los factores
de  bioacumulación derivados de  modelos de ecosistemas  a
corto  plazo indican un moderado potencial de acumulación.
Así pues, parece que el HEX y sus metabolitos no persisten
ni se acumulan en gran medida en los sistemas biológicos.

    Se ha demostrado que el HEX en  bajas  concentraciones
es  tóxico para los organismos acuáticos.  Se ha observado
letalidad en exposiciones agudas (48 a 96 h) en crustáceos
y peces de agua dulce y salada, en  concentraciones  nomi-
nales  de  32-180 µg/litro    en  sistemas  de  exposición
estática  en  los  que el  agua  no  se renovó  durante la
prueba.   Puesto que la semivida  fotolítica es < 1 h,  la
concentración  de  HEX  habría disminuido  sustancialmente
durante  el  periodo  de  exposición  utilizado  en   esos
estudios.  En los únicos estudios en los que se  usó  agua
corriente  y se midieron  las concentraciones de  HEX,  se
obtuvieron  valores de la CL50   en 96 horas de 7 µg   por
litro  en  Pimephales  promelas y  un camarón  de mar.  Los
ensayos realizados con esas dos especies dieron  un  valor
de CL10 de  3,7 y un valor de CL40 de  0,7 µg   por litro,

    En ensayos estáticos de siete días con  algas  marinas
se  observó una reducción  mediana del crecimiento  (CE50)
a  concentraciones  nominales  que variaron  entre  3,5  y
100 µg/litro, según la especie.

    En   medios  acuosos,  el  HEX   resulta  tóxico  para
numerosos  microorganismos en concentraciones nominales de
0,2-10 mg/litro,  es decir, niveles  sensiblemente mayores
que  los necesarios  para destruir  a la  mayoría  de  los
animales o vegetales acuáticos. El HEX parece menos tóxico
para  los microorganismos  en el  suelo que  en  el  medio
acuático,  probablemente a causa de la adsorción del HEX a
la matriz del suelo.

    Aunque  cabe esperar que  la exposición sea  reducida,
actualmente  no  se  dispone de  bastante información para
determinar  los efectos  de la  exposición al  HEX  en  la
vegetación o la fauna terrestres.

    La absorción de HEX sin modificar es mínima  debido  a
su  reactividad con las membranas y los tejidos del organ-
ismo y especialmente con el contenido del  tracto  gastro-
intestinal.   La  mayor  parte del  14C-HEX   radiomarcado
queda  retenido en el riñón,  el hígado, la tráquea  y los
pulmones  de los animales  tras la administración  por vía
oral, cutánea o respiratoria. El HEX absorbido  es  metab-
olizado y excretado rápidamente, sobre todo en  la  orina,
menos  en las heces y < 1% en el aire expirado.  El tiempo
de  eliminación terminal es  de unas 30 horas,  con  inde-
pendencia de la vía de administración.  Tras la inhalación
o  la administración intravenosa,  no se excreta  HEX  sin
modificar;  los  metabolitos  fecales y  urinarios  se han
aislado pero no se han identificado. La falta de identifi-
cación  de  los metabolitos  representa  uno de  los prin-
cipales  obstaculos para evaluar la  farmacocinética y los
mecanismos potenciales de acción del HEX.

    En la rata, la CL50   aguda por inhalación (durante un
periodo de aproximadamente 4 h) es de 17,9 mg/m3    en  el
macho  y 39,1 mg/m3   en  la hembra.  Aunque  hay  algunas
diferencias interespecíficas entre cobayos, conejos, ratas
y ratones, los vapores de HEX son sumamente  tóxicos  para
todas  las especies ensayadas.  Su toxicidad parece máxima
cuando se administra por inhalación, en comparación con la
administración  oral y cutánea, y es un irritante primario
fuerte.   Los efectos sistémicos  de la exposición  aguda,
con  independencia de la vía de administración, comprenden
cambios  patológicos en el pulmón,  el hígado, el riñón  y
las glándulas suprarrenales.

    La administración oral a corto plazo a ratas (38 mg/kg
al  día)  y  ratones  (75 mg/kg  al  día)  durante 91 días
produjo  nefrosis e inflamación e hiperplasia de la región
anterior del estómago. No se observaron signos manifiestos
cuando se expuso a ratas o ratones por inhalación  a  2,26
mg/m3    (0,2 ppm),  6 h/día,  5 días/semana,  durante  14

semanas.   Con 1,69 mg/m3   (0,15 ppm) sólo se observó una
ligera  irritación. La exposición de ratas a la inhalación
de  5,65 mg/m3    (0,5 ppm)  durante  30 semanas   provocó
cambios  histopatológicos en el hígado, el tracto respira-
torio  y el riñón.   En un estudio  de inhalación a  corto
plazo  de  HEX  en ratones  y  ratas  durante  90 días  se
observaron  efectos  en  el sistema  respiratorio  a  4,52
mg/m3   (0,4 ppm) o más.  No se ha demostrado que  el  HEX
sea  mutagénico en ensayos  in vitro , con  o sin activación
metabólica. También resultó inactivo en ensayos de letali-
dad dominante en el ratón.  Tampoco se ha  demostrado  que
sea teratogénico en ratas y ratones por  exposición  oral;
no  se dispone de datos  sobre la teratogenicidad del  HEX
tras la exposición por inhalación.

    Sólo se dispone de datos limitados sobre  los  efectos
de  la  exposición  al HEX  en  la  salud humana.   Se han
producido  incidentes aislados en  los que el  HEX provocó
fuerte irritación de los ojos, la nariz, la garganta y los
pulmones.  Por lo general esa irritación fue breve,  y  la
recuperación se inició en cuanto cesó la  exposición.   No
se  observaron diferencias estadísticamente significativas
en  ciertas  enzimas  hepáticas entre  grupos  expuestos y
grupos  testigo  tras la  exposición  a corto  plazo.   Se
desconocen los efectos a largo plazo en la salud humana de
la exposición continua a bajos niveles y/o  la  exposición
aguda intermitente. Se ha demostrado que los manipuladores
del  producto y de sus desechos, así como las personas que
trabajan  en la depuración de aguas residuales o que viven
en  las proximidades de  los lugares de  evacuación corren
riesgo  debido al potencial  de exposición a  la sustancia
química o a los residuos de su fabricación.

    La  base de datos no es lo bastante amplia ni adecuada
para  evaluar  la  carcinogenicidad del  HEX.  El Programa
Nacional de Toxicología de los EE. UU. ha llevado  a  cabo
un bioensayo de inhalación durante toda la vida en ratas y
ratones.   Cuando  se  publique el  informe patológico, se
comprenderá  mejor los efectos a largo plazo de la exposi-
ción  al HEX.  La evaluación de la carcinogenicidad deberá
demorarse  hasta que estén disponibles  los resultados del
bioensayo  del Programa. El Centro Internacional de Inves-
tigaciones  sobre  el  Cáncer evaluó  los datos existentes
para el HEX y clasificó la sustancia en el Grupo 3 (lo que
indica  que,  debido  a limitaciones  importantes de orden
cualitativo o cuantitativo, no puede interpretarse que los
estudios  demuestren ni la  existencia ni la  ausencia  de
efecto  carcinogénico).  En  la  bibliografía  se  citaron
varios  estudios epidemiológicos; no se notificaron aumen-
tos de la incidencia de neoplasmas en ninguna localización
que pudieran atribuirse al HEX o sus metabolitos.

    See Also:
       Toxicological Abbreviations
       Hexachlorocyclopentadiene (HSG 63, 1991)
       Hexachlorocyclopentadiene (ICSC)