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

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

    World Health Organization
    Geneva, 1990

         The International Programme on Chemical Safety (IPCS) is a
    joint venture of the United Nations Environment Programme, the
    International Labour Organisation, and the World Health
    Organization. The main objective of the IPCS is to carry out and
    disseminate evaluations of the effects of chemicals on human health
    and the quality of the environment. Supporting activities include
    the development of epidemiological, experimental laboratory, and
    risk-assessment methods that could produce internationally
    comparable results, and the development of manpower in the field of
    toxicology. Other activities carried out by the IPCS include the
    development of know-how for coping with chemical accidents,
    coordination of laboratory testing and epidemiological studies, and
    promotion of research on the mechanisms of the biological action of

    WHO Library Cataloguing in Publication Data

    Vinylidene Chloride.

        (Environmental health criteria ; 100)


        ISBN 92 4 154300 0        (NLM Classification: QV 633)
        ISSN 0250-863X

         The World Health Organization welcomes requests for permission
    to reproduce or translate its publications, in part or in full.
    Applications and enquiries should be addressed to the Office of
    Publications, World Health Organization, Geneva, Switzerland, which
    will be glad to provide the latest information on any changes made
    to the text, plans for new editions, and reprints and translations
    already available.

    (c) World Health Organization 1990

         Publications of the World Health Organization enjoy copyright
    protection in accordance with the provisions of Protocol 2 of the
    Universal Copyright Convention. All rights reserved.

         The designations employed and the presentation of the material
    in this publication do not imply the expression of any opinion
    whatsoever on the part of the Secretariat of the World Health
    Organization concerning the legal status of any country, territory,
    city or area or of its authorities, or concerning the delimitation
    of its frontiers or boundaries.

         The mention of specific companies or of certain manufacturers'
    products does not imply that they are endorsed or recommended by the
    World Health Organization in preference to others of a similar
    nature that are not mentioned. Errors and omissions excepted, the
    names of proprietary products are distinguished by initial capital


    1.1. Properties, uses, and analytical methods
    1.2. Sources and levels of exposure
    1.3. Absorption, distribution, metabolism, and excretion
    1.4. Effects on experimental animals and cellular systems
         1.4.1. Covalent binding to tissues
         1.4.2. Acute toxicity
         1.4.3. Short-term studies
         1.4.4. Long-term studies
         1.4.5. Genotoxicity and carcinogenicity
         1.4.6. Reproductive toxicity
    1.5. Effects on human beings


    2.1. Identity
    2.2. Physical and chemical properties
    2.3. Analytical methods


    3.1. Natural occurrence
    3.2. Production
    3.3. Uses
    3.4. Storage and transport


    4.1. Transport and distribution between media; degradation
         4.1.1. Air
         4.1.2. Water
         4.1.3. Soils and sediments
    4.2. Biodegradation
    4.3. Bioaccumulation


    5.1. Air
         5.1.1. Ambient air
         5.1.2. Occupational exposure
    5.2. Water
    5.3. Soil
    5.4. Food and food packaging


    6.1. Animals
         6.1.1. Absorption
        Inhalation exposure
        Oral exposure
         6.1.2. Distribution and storage

         6.1.3. Elimination
        Elimination of unchanged vinylidene chloride
        Elimination of metabolites
         6.1.4. Metabolic transformation
         6.1.5. Reaction with cellular macromolecules
         6.1.6. Transformation by non-mammalian species
    6.2. Human beings


    7.1. Effects on the stratospheric ozone layer
    7.2. Aquatic organisms


    8.1. Single exposures
         8.1.1. Inhalation
        Other animal species
         8.1.2. Oral 
         8.1.3. Other routes
        Eyes and skin
         8.1.4. Summary of acute toxicity
    8.2. Short-term exposures
         8.2.1. Inhalation
         8.2.2. Oral
    8.3. Long-term exposure
         8.3.1. Inhalation
         8.3.2. Oral
    8.4. Toxicity  in vitro 
    8.5. Mutagenicity and other genotoxicity assays
         8.5.1. Interaction with DNA
         8.5.2. Genotoxicity in bacteria
         8.5.3. Genotoxicity in yeast
         8.5.4. Genotoxicity in plants
         8.5.5. Genotoxicity in mammalian cells  in vitro 
         8.5.6. Genotoxicity in mammalian cells  in vivo 
         8.5.7. Summary
    8.6. Reproduction, embryotoxicity, and teratogenicity
    8.7. Carcinogenicity
         8.7.1. Inhalation
         8.7.2. Oral
         8.7.3. Other routes
         8.7.4. Summary of carcinogenicity


    9.1. Single and short-term exposures
    9.2. Long-term exposure

    10.1. Evaluation of effects on the environment
    10.2. Evaluation of human health risks 
         10.2.1. Levels of exposure
         10.2.2. Acute effects
         10.2.3. Long-term effects and genotoxicity


    11.1. Recommendations for future work
    11.2. Personal protection and treatment of poisoning
         11.2.1. Personal protection
         11.2.2. Treatment of poisoning in human beings







Dr M. Bignami, Laboratory of Ecotoxicology, Istituto Superiore di 
Sanita, Rome, Italy 

Mr J.F. Howlett, Food Science Division, Ministry of Agriculture, 
Fisheries & Food, London, England ( Chairman) 

Professor C.L. Galli, Institute of Pharmacological Sciences, 
University of Milan, Milan, Italy 

Professor E. Malizia, Emergency Toxicological Service, Antivenom 
Centre, Umberto the First Polyclinic, La Sapienza University, 
Rome, Italy 

Dr K. Chipman, Department of Biochemistry, University of 
Birmingham, Birmingham, England 

Dr Patricia S. Schwartz, Center for Food Safety and Applied 
Nutrition, Food & Drug Administration, Washington, DC, USA 

Professor I.V. Sanotsky, Research Institute of Industrial Hygiene & 
Occupational Diseases, USSR Academy of Medical Sciences, Moscow, 
USSR ( Vice-Chairman) 

Dr R. Frentzel-Beyme, Institute for Documentation Information 
and Statistics, DKFZ, Heidelberg, Federal Republic of Germany 
( Rapporteur) 

Dr J.F. Payne, Department of Fisheries and Oceans, St Johns, 
Newfoundland, Canada 

Dr J.C. Parker, Office of Health & Environmental Assessment, US 
Environmental Protection Agency, Washington, DC, USA 


Dr M.G. Penman, ICI Central Toxicology Laboratory, Macclesfield, 
Cheshire, England 

Dr Chr. de Rooij, Solvay & Cie SA, Brussels, Belgium 

Dr A. Mocchi, Centro Italiano Studi e Indagini (CISI), Rome, Italy 


Mr J. Wilbourn, Unit of Carcinogen Identification and Evaluation, 
International Agency for Research on Cancer, Lyons, France 

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


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

                              * * * 

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


A WHO Task Group on Environmental Health Criteria for Vinylidene 
Chloride met in Rome, Italy, from 3 October to 7 October 1988.  Dr 
E.  Smith opened the meeting on behalf of the Director-General.  The 
Task Group reviewed and revised the draft criteria document and 
made an evaluation of the health risks of exposure to vinylidene 

The drafts of this document were prepared by Dr J.K.  CHIPMAN, 
University of Birmingham, England.  Dr E.  SMITH, a member of the 
IPCS Central Unit, was responsible for the overall scientific 
content and Mrs M.O.  HEAD, Oxford, England, for the editing.  

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

                           * * * 

Financial support for the meeting was provided by the Ministry of 
the Environment of Italy; the Centro Italiano Studi e Indagini and 
the Istituto Superiore di Sanita, Rome, contributed to the 
organization and provision of meeting facilities.  

Partial financial support for the publication of this criteria 
document was kindly provided by the United States Department of 
Health and Human Services, through a contract from the National 
Institute of Environmental Health Sciences, Research Triangle Park, 
North Carolina, USA-a WHO Collaborating Centre for Environmental 
Health Effects.  

1.1.  Properties, Uses, and Analytical Methods

    Vinylidene chloride (C2H2Cl2) is a volatile, colourless
liquid with a "sweet" odour.  It is stabilized with  p- methoxyphenol 
to prevent the formation of explosive peroxides.  Vinylidene 
chloride is used for the production of 1,1,1-trichloroethane and
to form modacrylic fibres and copolymers (with vinyl chloride or 
acrylonitrile).  Gas chromatographic methods have been developed for
the determination of vinylidene chloride in air, water, packaging 
films, body tissues, food, and soil.  The most sensitive method of 
detection is by electron capture.  

1.2.  Sources and Levels of Exposure

    Up to approximately 5% of manufactured vinylidene chloride 
(representing an approximate maximum of 23 000 tonnes) is emitted 
into the atmosphere annually.  The high vapour pressure and low 
water solubility favour relatively high concentrations in the 
atmosphere compared with those in other environmental 
"compartments".  Vinylidene chloride in the atmosphere is expected 
to have a half-life of approximately 2 days.  

    Environmental levels in water are very low.  Even in raw 
industrial waste water, the concentrations rarely exceed the 
µg/litre range, which is well below the mg/litre range of toxicity 
for aquatic organisms.  The level in untreated drinking-water is 
generally not detectable.  In treated, potable water, the levels of 
vinylidene chloride have generally been found to be < 1 µg/litre, 
though levels of up to 20 µg/litre have been detected.  Levels of 
vinylidene chloride in food are usually not detectable, the 
maximum observed concentration being 10 µg/kg.  

    Occupational exposure to vinylidene chloride is mainly 
through inhalation, though skin or eye contamination can occur.  
Depending on the country, the maximum recommended or regulated 
time-weighted average (TWA) exposure limit is in the range of 8 to 
500 mg/m3, or else is the lowest reliably detectable 
concentration, depending on the country.  Short-term exposure 
limits range from 16 to 80 mg/m3 and ceiling values range from 50 
to 700 mg/m3.  
1.3.  Absorption, Distribution, Metabolism, and Excretion

    Vinylidene chloride can be readily absorbed via the 
respiratory and oral routes in mammals, but data are not available 
on dermal absorption.  Vinylidene chloride is widely distributed 
within the rodent body with concentrations reaching maximal 
levels in the liver and kidneys.  The pulmonary elimination of 
unchanged vinylidene chloride is at least biphasic and dose 
dependent, being of greater importance at dose levels that saturate 
metabolism (approximately 600 mg/m3 (150 ppm) via inhalation in 
the rat).  Fasting of rats led to a reduction in the metabolism of 
an oral dose and a consequent higher level of exhaled vinylidene 

    The major routes of metabolism in the rat have been 
characterized.  The predominant phase I metabolism involves 
cytochrome P-450 and the formation (possibly but not necessarily 
via an epoxide) of mono-chloroacetic acid.  Cytochrome P-450 
activity can be induced by vinylidene chloride.  A number of phase 
I metabolites are conjugated with glutathione and/or with 
phosphatidyl ethanol-amine prior to further conversions.  
Metabolism occurs at a greater rate in the mouse than in the rat 
resulting in a similar metabolic profile with a relatively higher 
proportion of glutathione conjugate derivatives.  It has been shown 
that vinylidene chloride is also metabolized by human microsomal 
cytochrome P-450.  Metabolism of vinylidene chloride in rodents 
leads to depletion of glutathione and inhibition of the activity of 
glutathione- S -transferase.  
1.4.  Effects on Experimental Animals and Cellular Systems

1.4.1.  Covalent binding to tissues

    Covalent binding of [14C]-vinylidene chloride-derived 
radiolabel occurs in the liver, kidney, and lung of rodents 
and is associated with toxicity in these organs.  Covalent binding 
and toxicity are exacerbated by glutathione depletion and occur 
in the liver and kidney at a lower dose level in mice than in rats.  
A number of vinylidene chloride metabolites covalently bind to 
thiols  in vitro .  
1.4.2.  Acute toxicity

    Acute LC50 estimations for vinylidene chloride vary 
considerably, but this variation does not mask the fact that mice 
are much more susceptible to vinylidene chloride than rats or 
hamsters.  Estimations of 4-h LC50 values ranged from 
approximately 8000 to 128 000 mg/m3 (2000-32 000 ppm) in fed rats, 
460-820 mg/m3 (115-205 ppm) in fed mice, and 6640-11 780 mg/m3 
(1660-2945 ppm) in fed hamsters.  Inaccuracies in LC50 
estimations may arise because of a non-linear concentration- 
mortality relationship.  Males of all species tended to have lower 
LC50 values than females, and fasting (which causes depletion of 
glutathione) increased toxicity in all three species.  LD50 values 
following oral administration were approximately 1500 and 200 mg/kg 
in fed rats and mice, respectively.  Acute inhalation toxicity 
in experimental animals was manifested as irritation of the 
mucous membranes, depression of the central nervous system, and 
progressive cardiotoxicity (sinus bradycardia and arrhythmias).  
Damage was caused to the liver, kidney, and lungs.  In mice, which 
are more susceptible than rats to the hepatotoxicity and renal 
toxicity of vinylidene chloride, kidney damage and increased DNA 
replication were induced by exposure to as little as 40 mg 
vinylidene chloride/m3 (10 ppm) for 6 h.  As with inhalation, the 
principal organs affected by oral administration of vinylidene 
chloride are the liver, kidney, and lungs.  The sequelae of events 
leading to hepatotoxicity appear to involve an early change in the 
bile canaliculi, which is followed by signs of mitochondrial 
damage.  This precedes damage to the endoplasmic reticulum and cell 

death.  Vinylidene chloride-induced liver and renal toxicity are 
apparently not caused by lipid peroxidation.  Raised intracellular 
Ca++ concentrations may play a role in toxicity for the 
    The toxic effects of vinylidene chloride are at least 
partially dependent on cytochrome P-450 activity (which may also be 
involved in detoxification) and can be exacerbated by glutathione 
depletion.  Hepatotoxicity may be enhanced by ethanol and 
thyroxine, inhibited by dithiocarb and (+)-catechin, and modulated 
by acetone.  

1.4.3.  Short-term studies

    Hepatic, renal, and, to a lesser extent, pulmonary damage have 
been observed in rodents exposed through inhalation to vinylidene 
chloride at 40-800 mg/m3 for 48 h/day, 4 or more days/week, in 
short-term studies.  Mice were more susceptible than rats, guinea-
pigs, rabbits, dogs, and squirrel monkeys, and toxicity varied 
between different strains of mice.  In general, female mice were 
less susceptible than males.  Hepatotoxicity was reported in rats 
and mice exposed intermittently to vinylidene chloride 
concentrations of > 800 mg/m3 (> 200 ppm) or 220 mg/m3 (55 
ppm), respectively.  The levels required to produce 
hepatotoxicity through continuous exposure for several days were 
240 mg/m3 (60 ppm) for rats and 60 mg/m3 (15 ppm) for mice.  These 
intermittent and continuous treatments also caused nephrotoxicity 
in mice.  The male Swiss mouse was particularly susceptible to 
vinylidene chloride-induced kidney toxicity.  Male mice did not 
survive continuous short-term exposure to 200 mg vinylidene 
chloride/m3 (50 ppm).  The apparent no-observed-effect level for 
hepatotoxicity in dogs, squirrel monkeys, and rats was 
approximately 80 mg/m3 (20 ppm) given as a continuous 90-day 
exposure.  Short-term (approximately 3 months) oral dosing studies 
in rats (up to 20 mg/kg daily) and dogs (up to 25 mg/kg daily) did 
not show any evidence of toxicity other than minimal reversible 
hepatic damage in rats.  

1.4.4.  Long-term studies

    Long-term studies of intermittent inhalation exposure to 
vinylidene chloride revealed that 300 mg/m3 (75 ppm) caused only 
mild reversible hepatic changes in rats.  At 600 mg/m3 (150 ppm), 
the highest tolerable dose for long-term exposure in rats, liver 
damage with necrosis was evident.  A high mortality rate with 
evidence of liver damage was observed in mice at 200 mg/m3 (50 
ppm).  Kidney toxicity was evident following long-term treatment of 
mice at 100 mg/m3 (25 ppm).  Oral dosing of rats for one year with 
up to 30 mg vinylidene chloride/kg daily also produced minimal 
hepatic changes.  These data do not provide a clear no-observed-
effect level.  There was some evidence from a separate study that 
renal inflammation and liver necrosis could be induced in rats 
and mice, respectively, following long-term oral administration of 
vinylidene chloride at daily dose levels of 5 mg/kg and 2 mg/kg, 

1.4.5.  Genotoxicity and carcinogenicity

    Vinylidene chloride was found to be mutagenic for bacteria and 
yeast, only in the presence of a mammalian microsomal metabolic 
activation system (S9).  The compound induced unscheduled DNA 
synthesis in isolated rat hepatocytes and increased the frequency 
of sister chromatid exchanges and chromosomal aberrations in cell 
cultures with S9 included.  In contrast, no increase in mammalian 
gene mutations was seen.  A small, but statistically significant, 
increase in DNA binding after  in vivo exposure has been reported.  
DNA binding was greater in mouse than in rat cells and greater in 
the kidneys than in the liver following 6-h exposures to 40 and 200 
mg vinylidene chloride/m3 (10 and 50 ppm).  Furthermore, 
vinylidene chloride slightly increased unscheduled DNA synthesis 
in mouse kidney.  There was no evidence of a dominant lethal 
effect or cytogenetic effects after  in vivo exposure of rodents, 
with the exception of one study showing the induction of 
chromosomal aberrations in the bone marrow of the Chinese hamster.  

    Carcinogenicity studies have been carried out on 3 animal 
species (rats, mice, and hamsters).  In male Swiss mice, there was 
a clear indication of carcinogenicity (kidney adenocarcinoma) 
following long-term intermittent exposure to 100 or 200 mg 
vinylidene chloride/m3 (25 or 50 ppm) but not to 0 or 40 mg/m3
(0 or 10 ppm).  

    The kidney tumours may be related in some way to observed 
kidney cytotoxicity and it is possible that repeated kidney 
damage either leads directly to the carcinogenic response by a 
non-genotoxic mechanism or facilitates the expression of the 
genotoxic potential of metabolites in this particular species, sex, 
and organ.  However, this conclusion is uncertain in the light of 
the limited available data on genetic effects  in vivo and the 
findings that vinylidene chloride may have acted as an initiator.  

    In the same study, statistically increased incidences of lung 
tumours (mainly adenomas in mice of both sexes) and mammary 
carcinomas (in females) were observed, but no dose-response 
relationships were found.  In adult rats exposed through inhalation, 
a slight non-dose-related increase in mammary tumours was 
reported as well as a slight increase in leukaemia when rats 
were exposed  in utero and then postnatally.  These observations 
could not be evaluated.  

1.4.6.  Reproductive toxicity

    No evidence was found of effects on fertility in rats 
continuously exposed to vinylidene chloride (up to 200 mg/litre, 
200 ppm) in drinking-water.  Inhalation of up to 1200 mg vinylidene 
chloride/m3 (300 ppm), for 22-23 h, by rats and mice during 
various periods of organogenesis did not induce fetal 
abnormalities, other than those attributable to maternal 

    Inhalation of up to 640 mg vinylidene chloride/m3 (160 ppm) 
for 7 h/day in rats and rabbits or oral intake of approximately 
40 mg/kg per day in rats during critical periods of gestation did 
not have any effects on embryos or fetuses at a level below that 
which produced maternal toxicity, but embryo and fetal toxicity 
and fetal abnormalities were seen at levels producing maternal 
toxicity, as evidenced by decreased weight gain.  

1.5.  Effects on Human Beings

    Concentrations of vinylidene chloride of 16 000 mg/m3 
(4000 ppm) cause intoxication that may lead to unconsciousness.  
Stabilized vinylidene chloride is also an irritant for the 
respiratory tract, eyes, and skin.  Kidney and liver damage have 
been reported for sub-anaesthetic, prolonged or repeated short-term 
exposures.  Evaluation of epidemiological studies was hampered by 
limited cohort sizes, co-exposure to vinyl chloride, and 
insufficient attention to smoking habits.  No statistically 
significant increased incidence of cancer was found in human 
beings exposed to vinylidene chloride, but the epidemiological 
studies were inadequate and it is not possible to conclude that 
there is no carcinogenic risk.  No information is available on the 
effects of vinylidene chloride on reproduction in human beings.  

2.1.  Identity

    Vinylidene chloride is a halogenated aliphatic hydrocarbon.  

Chemical             Cl   H
structure:           |    |
                     C  = C
                     |    |
                     Cl   H

Molecular            C2H2Cl2
molecular mass:      96.95 

Common               1,1-dichloroethylene; 1,1-dichloroethene; 
synonyms:            1,1-dichloro; VDC; 1,1-DCE; VC; vinylidene 
                     dichloride; chlorure de vinylidene (France); 
                     asym-dichloroethylene; NCI-C54262 
Common trade 
name:                Sconatex 
IUPAC systematic 
name:                1,1-dichloroethylene 

NCI number:          C54262 
CAS registry 
number:              75-35-4 
RTECS number:        KV9275000 
EEC number:          602-025-00-8 
Conversion           1 ppm vinylidene chloride = 4 mg/m3 
factors:             1 mg vinylidene chloride/m3 = 0.25 ppm
                     at 25 °C, 1 atm.  

 Commercial vinylidene chloride 

    The technical product (which is > 99.6% pure) can contain 
impurities (Table 1).  

Table 1.  Maximum levels of impurities found in 
commercial vinylidene chloridea
Dichloroacetylene                10 mg/kg

Monochloroacetylene              1 mg/kg

Vinyl chloride                   20 mg/kg

Water                            100 mg/kg

Acidity  (as HCL)                15 mg/kg

Iron                             0.5 mg/kg

Peroxides (as H202)              1 mg/kg

Other halogenated impurities     500 mg/kg (total)
a  From: ECETOC [45].

 Note: Hydroquinone monomethyl ether ( p- methoxy- 
phenol) is the most commonly used inhibitor, which is 
added at a level of 50-200 mg/kg.  The carcinogen 
dichloroacetylene may also occur as an impurity, as it 
is a by-product of vinylidene chloride synthesis [185].

2.2.  Physical and Chemical Properties

    The principal physical and chemical properties of 
vinylidene chloride are shown in Table 2.  

Table 2.  Some physical and chemical properties of vinylidene chloridea
Physical form             volatile, clear, colourless liquid; it 
                          polymerizes readily in the presence of 
                          oxygen above 0 °C 

Odour                     "sweet" odour; apparent detection limit 
                          for human beings, approximately 2000-4000 

Boiling point (°C)        31.56

Freezing point (°C)       -122.5

Relative  density        
(20 °C/40 °C)             1.213 

Vapour density 
(air = 1, 20 °C)          3.34

Density in saturated      2.8
air (air = 1)
Table 2 (contd).
Vapour pressure (mmHg) 
at:     -20 °C            7        
          0 °C            215      
         20 °C            495      
         25 °C            591      

Refractive index (ND) 
(20 °C)                   1.4247

Viscosity (P x s) (20 °C) 0.3302

Critical temperature (°C) 220.8

Critical pressure (atm)   51.3

Heat of combustion        261.9 (liquid monomer)
(kcal/mol) (25 °C)

Heat of formation         -25.1 (liquid monomer)
(kcal/g)                  1.26 (gaseous monomer)

Solubility in water 
(21 °C)                   2.5 g/kg
Solubility in organic     very soluble-diethyl ether, chloroform
 solvents:                soluble-benzene, acetone, ethanol     
Calculated log  n -octanol/
 water partition 
 coefficient              1.66c
Flash point (open cup)    -15 °C
            (closed cup)  -19 °C

Flammability limits in 
 air (% vol)              5.6-16

Saturation concentration
 in air (20 °C)           2640 g/m3

 temperature (°C)         513

Heat of evaporation 
 (31.6 °C) (cal/mol)      6.3

Heat of polymerization 
 (25 °C) (kcal/mol)       18
a  From: Buckingham [22],  Gibbs & Wessling [59], Hushon & Kornreich
   [84], Shelton et al.  [201], Weast [241], and Wessling & Edwards [243], 
   unless stated otherwise.
b  From: Torkelson & Rowe [222].
c  From: Rekker [187].

    In the absence of a stabilizer and in the presence of oxygen, 
vinylidene chloride forms an explosive peroxide at temperatures  
as low as -40 °C [22].  The decomposition products of vinylidene 
chloride peroxides include phosgene, formaldehyde, and 
hydrochloric acid [59].  Vinylidene chloride also reacts vigorously 
with oxidizing materials and is highly dangerous when exposed to 
heat or flame [197].  It undergoes addition reactions as in the 
formation of 1,1,1-trichloroethane when it is reacted with hydrogen 
chloride.  Alcohols and halides react with vinylidene chloride to 
give carboxylic acids [22].  Vinylidene chloride will react with 
aluminium to form reactive aluminium chloroalkyls, and copper can 
form reactive acetylides from its interaction with acetylenic 
impurities.  In the presence of a polymerization initiator, 
vinylidene chloride forms homopolymers and copolymers with other 
vinyl monomers [59].  

2.3.  Analytical Methods

    Some spectral features of vinylidene chloride are shown in 
Table 3.  Vinylidene chloride is well suited to liquid and 
headspace sampling and determination by gas chromatography.  Details 
of sampling, preparation, and the determination of vinylidene 
chloride in different media are given in Table 4.  The major 
analytical limitation is interference by other constituents of the 

Table 3.  Ultraviolet absorption and mass spectroscopic 
characteristics of vinylidene chloride
UV absorption maximum     200 vapa

Mass spectrum             61  (100)  96  (61)b     
                          98  (38)   63  (32)   
                          26  (16)   60  (15)         
                          25  (7)    35  (6)    
a  From: Weast [241].
b  From: Grasselli & Ritchey [63].

Table 4.  Sampling, preparation, and determination of vinylidene chloridea
Medium     Sampling               Analytical       Detection     Comments                         Refer-
           method                 methodb          limit                                          ence
Air        Cold trap (liquid 02)                                 Introduction of a sorbent trap   [212]
           using column of                                       allows a large sample; however,
           glass beads; desorb                                   cumbersome for handling
           thermally by purge
           Trap with pyridine     Colourimetric    10 mg/m3                                       [66]
           in cooled impinger     measurement of

           Trap with charcoal;    GC/FID           1 µg/m3       Well suited for monitoring       [50]
           desorb with CS2                         (7 µg/sample  occupational exposure levels;    [205]
                                                   tube)         trapped vinylidene chloride is   [80]
                                                                 stable for at least 16 days;
                                                                 when desorbed in CS2, analysis
                                                                 should be within 4 days;
                                                                 humidity dramatically reduces
                                                                 the breakthrough volume

           Trap with adsorbent    GC/FID           4 µg/m3                                        [191]
           column; desorb                                                                         (see 
           thermally                                                                              also  

           Trap with charcoal     GC/FID           working range                                  [226]
           desorb with CS2                         2-20 mg/m3 for a
                                                   5- to 7-litre sample
           Trap with Tenax        GC/MS            0.12 µg/m3    Suitable for monitoring          [233]
           polymer; desorb                         (0.6 µg/m3,   environmental samples
           thermally                               quantifiable

Human      Spirometer used for    GC/MS            0.16 µg/m3                                     [233]
breath     sampling; trap and                      (0.82 µg/m3,
           desorb as above                         quantifiable

Table 4 (contd).
Medium     Sampling               Analytical       Detection     Comments                         Refer-
           method                 methodb          limit                                          ence
Human      As above using         GC/MS            0.16 µg/m3                                     [233, 
breath     liquid nitrogen                         (0.82 µg/m3                                    234]
           cryogenic trap                          quantifiable 
Vinyl      Distillates            GC/FID           5 mg/kg                                        [107]

Waterc     Direct injection       Steam-modified   approx.       Obvious advantages of            [67]
                                  G-solid C/FID    5 µg/litre    direct injection but rapid 
                                                                 deterioration of column
           Direct headspace       GC/FID           2 µg/litre                                     [171]
           analysis (purge and    confirmation      
           trap between water     by MS

           Dynamic headspace      (a) GC/FID       (a) 0.5 µg/litre                               [162] 
           technique              (b) GC/ECD       (b) 0.1 µg/litre

           Static headspace       GC/FID           5 µg/litre                                     [164]
           technique                               (quantifiable
                                  GC/ECD           10 µg/litre

           Purge with inert       GC/ECD           0.13 µg/      A microcoulometric detector      [223]
           gas; trap (Tenax);                      litre         can also be used; direct 
           desorb as vapour                                      aqueous injection above 
                                                                 0.13 mg/litre

                                  GC/FID and       1 µg/litre    Linearity shown for response     [17]
                                  EC                             versus concentration between 
                                                                 10 µg/litre and 1 mg/litred      [234]

Table 4 (contd).
Medium     Sampling               Analytical       Detection     Comments                         Refer-
           method                 methodb          limit                                          ence
Water      As above with isotope- GC/MS            10 µg/litre   Internal standard corrects for   [224]
(contd.)   labelled vinylidene                                   variability in recovery
           chloride as internal

           Headspace transfer     GC/EC            0.03 µg/      Sensitive and inexpensive-       [31]
           (vacuum distillation)                   litre         recommended for field
           to cryogenic trap                                     conditions

           Purge-closed loop      GC/EC, EDC,      0.2 µg/litre  Combines gas-stripping and       [236]
           method                 or FID (most     (20-ml        static headspace methods - 
                                  efficient        sample)       recommended as an effective, 
                                  not indicated)                 reliable and rapid method for 
                                                                 routine sample analysis

Packaging  Films dissolved in     G-solid C/EC     5 mg/kg       Injection port needs cleaning    [18]
materials  tetrahydrofuran or     confirmation                   regularly 
(Saran     carbon tetrachloride;  by MS            1 mg/kg                                        [78]
films)     can be injected with

                                  GC/MS            1 mg/kg                                        [144, 
           Vinylidene chloride    GC/FID                         Requires internal standard of    [62]
           released thermally;                                   polymer with known content 
           sample by headspace                                   of vinylidene chloride

           Headspace technique    GC/EC            1 µg/m2                                        [60]

Food       Headspace technique    G-solid C/EC     5-20 µg/kg                                     [78]
simulating                        confirmation
solvents                          by MS
exposed to      
Saran films                       GC/EC            1 µg/kg                                        [238]
(corn oil,
heptane, and

Table 4 (contd).
Medium     Sampling               Analytical       Detection     Comments                         Refer-
           method                 methodb          limit                                          ence
Food       Headspace technique    GC/EC            5 µg/kg                                        [60]
Body       Minced tissue added    GC/ECD           approximately Well suited for pharmaco-        [125]
tissues    to iso-octane/water;                    10 µg/kg      kinetic studies; specific
(various)  purge (helium);                         (limit of     purging method avoids 
           trap (Tenax);                           detection of  foaming
           desorb as vapour                        injected 
                                                   50 pg)

Body       Tissue homogenized;    GC/MS            10 µg/kg      Recovery reported better by      [44]
tissue     purge and trap                                        vacuum distillation method
(fish)     procedure                                                                              [76]

Soil       Extract ( n- hexa-      GC/EC            10 µg/kg                                       [37]
           decane); add internal

Sediment   Sealed in vial with    GC/EC            5 µg/kg       Minimum recovery observed        [214]
           internal standard;                                    = 67%
           purge with inert
           gas; trap (Tenax);
a  Methods for grab sampling of air are not included, since these do not allow estimations of 
   time-weighted average values; laser Stark spectroscopy [215] or portable infrared analysers [50] give 
   poor sensitivity and specificity due to interference by other halohydrocarbons.

b  GC = gas chromatography; FID = flame ionization detection; EC = electron capture; 
   EDC = electrolytic conductivity; MS = mass spectroscopy.

c  If the sample contains chlorine, sodium thiosulfate should be added to prevent chlorination of 
   hydrocarbons [17].  

d  From: Ramstad et al.[181].
3.1.  Natural Occurrence

    Vinylidene chloride is not known to occur naturally.  

3.2.  Production

    Crude vinylidene chloride is produced by the treatment of 
1,1,2-trichloroethane with sodium hydroxide or calcium hydroxide.  
Fractional distillation of the washed and dried crude product 
provides the commercial vinylidene chloride to which a stabilizer 
(usually  p- methoxyphenol) is added to prevent polymerization [59, 

    Vinylidene chloride has also been shown to be produced in 
substantial quantities from the thermal decomposition of methyl 
chloroform [61].  Methyl chloroform vapours (1910 mg/m3) 
decomposed to vinylidene chloride at temperatures above 350 °C and 
180 °C in the absence and presence of copper, respectively.  The 
extent to which this dehydrohalogenation occurs in work 
environments leading to human exposure to vinylidene chloride is 
not known.  It has been demonstrated [220] that 1,1,1,2-tetrachloro-
ethane is readily converted to vinylidene chloride  in vivo in the 
rat by reductive metabolism.  Thus, 1,1,1,2-tetrachloroethane is a 
potential source of bioavailable vinylidene chloride.  In addition, 
vinylidene chloride is a major aqueous abiotic degradation 
product of a frequent contaminant of ground water, namely 1,1,1-
trichloroethane [169, 230].  

    In 1967, world production of vinylidene chloride was estimated at 
220 000-330 000 tonnes [201].  The following annual world production 
rates of vinylidene chloride (in thousands of tonnes) have been 
reported for the early 1980s [86]: the Federal Republic of 
Germany, 100; France, 50; Japan, 23; the Netherlands, 12; the 
United Kingdom, 30; and the USA, 90.7.  This totals 306 000 tonnes.  
The estimates should be taken as very approximate and it is likely 
that the production level has now decreased [86].  A recent 
estimate of worldwide production is 290 000 tonnes annually: in 
Western Europe, approximately 80% of the vinylidene chloride 
produced is for internal use by the companies concerned (personal 
communication: European Chemical Industry Ecology and Toxicology 

3.3.  Uses

    Vinylidene chloride is used for the production of 
1,1,1-trichloroethane and to form modacrylic fibres and 
copolymers (Saran(R)) with alkyl acrylates, methacrylates, 
acrylonitrile, vinyl acetate, or vinyl chloride [59].  Vinylidene 
chloride/vinyl chloride copolymers (Saran(R) B) are used for the 
packaging of foods, as metal coatings in storage tanks, building 
structures, and tapes, and as moulded filters, valves, and pipe 
fittings.  These copolymers are also used to reinforce polyesters, 
inks, and composites for furniture upholstery and other 

constructions.  Polyvinylidene chloride or vinylidene chloride 
copolymerized with acrylic esters or with acrylonitrile and 
acrylic esters (Diofane(R)) are used for coating paper and board 
and as flame-retardant binders in other coatings.  It is prohibited 
in the EEC to include vinylidene chloride in cosmetics [88].  
Regulations in the USA [88] restrict the vapour concentration of 
vinylidene chloride to 25% of the lower explosive limit when used 
in spray finishing operations.  

3.4.  Storage and Transport

    The storage and transport of vinylidene chloride may be sources 
of exposure; however, reports of such exposure have not been found 
in the literature.  Vinylidene chloride should not be stored for 
more than a day without a stabilizer [59], which does not need to 
be removed prior to use in polymer syntheses.  The monomer should be 
blanketed with inert gas, stored (e.g., hermetically sealed steel 
containers) at a maximum of -10 °C and protected from light, air, 
free radical initiators, copper, and aluminium [201] (section 2.2).  
Under these conditions, inhibited vinylidene chloride can be 
transported and stored, though the length of the storage period 
should be minimal.  A water-spray system should be available for 
cooling the tanks in the event of fire.  Containers of vinylidene 
chloride must be appropriately labelled.  In the EEC, the following 
labels apply: extremely flammable, harmful by inhalation, possible 
risk of irreversible effects, keep container tightly closed, keep 
away from sources of ignition, no smoking, do not empty into drains 
[88].  Any industrial waste containing this substance must be listed 
as hazardous and is therefore subject to handling, transport, 
treatment, storage, and disposal regulation.  Disposal should be by 
incineration and not by discharge into sewers.  Complete combustion 
should be ensured to prevent the formation of phosgene.  An acid 
scrubber should be used to remove the halo-acids produced.  
Vinylidene chloride-derived peroxides can be detected by the 
liberation of iodine following the addition of acidified 
isopropanol saturated with sodium iodide and can be destroyed by 
contact with water at room temperature [201].  

4.1.  Transport and Distribution Between Media, Degradation

4.1.1.  Air

    The high vapour pressure and low water solubility of 
vinylidene chloride favour relatively high atmospheric 
concentrations compared with other environmental "compartments".  
Atmospheric radicals will play a major role in the degradation of 
vinylidene chloride.  The rate constant for oxidation of 
vinylidene chloride with hydroxyl radicals (the major reacting 
radical) was reported to be 4 x 10-12 cm3/mol per second [34].  
Judging by this and the half-lives of related chlorinated ethenes 
reacting with hydroxy radicals, the half-life of vinylidene 
chloride reacting with tropospheric hydroxyl radicals (assumed to 
be 10-6 radicals/cm3) is expected to be approximately 2 days.  
Degradation by reaction with other atmospheric radicals will 
also take place.  Vinylidene chloride may react with chlorine 
atoms derived from chloro-olefins, peroxy radicals (estimated half-
life for this reaction in the atmosphere is 22 years; [20]) and 
ozone (estimated half-life is 219 days; [225]).  The gas-phase 
ozonolysis of vinylidene chloride at 25 °C follows second-order 
kinetics and appears to involve a chain mechanism the chain carrier 
being C Cl2O.  The products of the reaction are C Cl2O, HCOOH, 
CH2ClCCl(O), CO, O2, HCl, and H2O [83].  The chloroacetyl chloride 
is most likely formed by a rearrangement of 1,1-dichloroethylene 
oxide [58].  The measured half-life of vinylidene chloride within 
sealed quartz flasks exposed outdoors in the northwest of England 
[169] was higher than expected from the information given above (56 
days).  However, the relevance of these data to the environmental 
persistence of vinylidene chloride is difficult to interpret 
considering the high concentration used (80 mg/m3) and the specific 
conditions of exposure.  

   The very long half-lives estimated for removal by rain droplets 
(1.1 x 105 years) or by adsorption on aerosol particles (1.5 x 108 
years) indicates that these processes are insignificant [34].  

4.1.2.  Water

   Consideration of the physical and chemical properties of 
vinylidene chloride (section 2.2) suggests that volatilization is 
the major transport process from water [46].  Dilling [40] measured 
the half-life for the evaporation of vinylidene chloride (1 mg/ml) 
from a stirred aqueous solution at 25 °C and with a depth of 6.5 
cm.  The value obtained (27.2 min) was remarkably close to the 
calculated value (20.1 min).  Using the calculated re-aeration rate 
constant for vinylidene chloride and oxygen [127], a half-life can 
be calculated of between approximately 6 days (static pond water) 
and approximately 1 day (mobile river water).  

    Photolysis and hydrolysis are not likely to be significant 
[127], though degradation of vinylidene chloride in water contained 
in sealed bottles in the dark was apparently measurable (albeit 

slow) in the study by Pearson & McConnell [169].  The dispersal 
of vinylidene chloride was monitored by Wang et al.  [236] 
following its discharge and mixing into a drainage canal that led 
to a river 1.5 km downstream.  The maximum discharge water 
concentration of vinylidene chloride was 36.7 µg/litre.  Midway 
canal water concentrations of vinylidene chloride were not only 
dependent on the concentration in the discharged water but were 
also inversely related to the canal flow rate.  The highest midway 
canal water concentration was 1.4 µg/litre, which arose from a 
discharged concentration of 16.7 µg/litre with a canal flow 
rate of about 200 litres/second.  At the site of confluence of 
the canal and river, the levels of vinylidene chloride were 
consistently less than 0.2 µg/litre (detection limit).  
4.1.3.  Soils and sediments

    Few data are available on the transport or persistence of 
vinylidene chloride in soils and sediments.  

    The transformation of vinylidene chloride was studied in 
anoxic microcosms containing organic sediment collected from the 
Everglades in Southern Florida [13].  The first order rate constant 
of dehalogenation was 3.57 x 10-4 h-1 for surficial sediment and 
1.67 x 10-4 h-1 for bottom sediments.  Transformation products 
included low levels of vinylidene chloride but mechanisms of 
transformation other than reductive dechlorination occurred.  The 
log  n- octanol/water partition coefficient of 1.66 [187] and the 
significant solubility of vinylidene chloride in water (2.5 
g/litre) suggest that some leaching from soils may occur.  As with 
water, volatilization is expected to be a major process of removal.  
    Relatively high concentrations of vinylidene chloride (1600± 
400 µg/litre) have been reported in municipal wastewaters (primary 
treatment waters) in Orange Country, California [246].  However, 
quantifiable concentrations of vinylidene chloride (> 5 µg/kg) 
were not found in sediments in the outfall area.  

4.2.  Biodegradation

    Tabak et al.  [217] measured a microbial degradation of 78% of 
vinylidene chloride (5 mg/litre) following 7 days incubation at 
25 °C in a static culture flask, in the dark, with settled domestic 
waste water as microbial inoculum.  With subsequent incubations 
(after adaptation), 100% loss of compound occurred.  At 10 mg 
vinylidene chloride/litre, 45% loss was found in the first 7 days 
incubation.  Volatilization losses over 7 days at 25 °C were 24 
and 15% at 5 and 10 mg/litre, respectively.  Activated sludge 
treatment of waste water resulted in 97% removal of vinylidene 
chloride at an inflow concentration of 0.04 mg/litre [168].  These 
data suggest a possible role of biodegradation; however, the 
evidence is not conclusive and volatilization may be responsible 
for some of the measured losses from the hydrosphere (inadvertent 
in the former study).  

    Recently, a mixed culture of methane-utilizing bacteria was 
found to degrade vinylidene chloride from 630 to 200 µg/litre 
following incubation in sealed culture bottles for 48 h.  The 
products were non-volatile chlorinated substances and the 
corresponding amount of degradation using a dead culture was from 
520 to 350 µg/litre [51].  Vogel & McCarty [230] have reported 
that anaerobic microorganisms can completely convert vinylidene 
chloride to vinyl chloride by reductive dehalogenation.  Vinyl 
chloride can subsequently be mineralized to carbon dioxide.  

4.3.  Bioaccumulation

    Bioaccumulation is expected to be low, based on the 
 n- octanol/water partition coefficient and the water solubility 
(Table 2).  A bioconcentration factor of 4 and a bioaccumulation 
factor of 6.9 were reported for fish in a review by Atri [9].  

5.1.  Air

5.1.1.  Ambient air

    In an assessment of vinylidene chloride emission in the USA 
[84], an annual release of a total of 599 tonnes was estimated 
from production and polymerization operations.  A more recent 
estimate of this emission is placed at a much lower level of 93.5 
tonnes (personal communication, US Chemical Manufacturers
Association, 1987).  It was estimated that between 2 and 5% of
vinylidene chloride manufactured in the USA was emitted into the
air (20-50 tonnes per 1000 tonnes produced) [212] but, on the
basis of current experience, the emissions into the air are of the
order of 1%.  With an annual global production of around 300 000
tonnes, the total emissions would be 3000 tonnes per year
(personal communication, European Chemical Industry Ecology and
Toxicology Centre).  
    Vinylidene chloride levels detected in ambient air from a 
petrochemical manufacturing area and a non-industrial centre, 
respectively, ranged from 0.06 to 416.07 µg/m3 (mean, 46.84 µg/m3) 
and from 3.53 to 27.29 µg/m3 (mean, 11.21 µg/m3) [233].  There was, 
therefore, marked variability.  The concentrations in the breath 
of human individuals in the respective areas were in the ranges of 
0.08-25.17 µg/m3 and 3.94-14.12 µg/m3.  The data suggested a log-
linear relationship between air and breath concentrations of 
vinylidene  chloride (section 6.2).  Hushon & Kornreich [84] 
reported the results of a US EPA ambient air sampling programme.  
Concentrations of vinylidene chloride ranged from not 
detectable to a maximum of 0.010 mg/m3.  In the rural northwest of 
the USA, in the mid 1970s [65], vinylidene chloride levels in air 
were non-detectable (< 20 ng/m3; < 5 ppt), which is in 
accordance with the short half-life estimated for vinylidene 
chloride in the atmosphere (section 4.1.1).  At the perimeters of 
industrial sites in the USA, air levels ranged from non- 
detectable up to 52 µg/m3 [62] 0.6 miles from the site being the 
maximum distance for the detection of vinylidene chloride.  In urban 
environments in the USA, mean air concentrations were found to be 
19.6, 50.4, and 119.2 ng/m3 (4.9, 12.6, and 29.8 ppt) [212].  These 
authors estimated average daily doses of 0.4, 1.1, and 2.5 µg/day, 
respectively, at these sites, based on a total air intake of 23 
m3/day.  In a subsequent study [213] of seven additional cities in 
the USA, concentrations ranged from below the detection limit (20 
ng/m3; 5 ppt) to 0.224 µg/m3, with arithmetic averages ranging 
from 0 to 0.123 µg/m3.  The median concentration of vinylidene 
chloride in the seven cities was 0.036 µg/m3.  Wallace et al.  [235] 
reported a 5-year US EPA study in urban populations of personal 
exposures to vinylidene chloride amongst many other pollutants.  A 
total of nearly 5000 air, breath, and drinking-water samples were 
collected for 400 respondents in New Jersey, North Carolina, and 
North Dakota.  The median coefficients of variance for the analysis 
of air and breath samples was 20-40%.  Vinylidene chloride was 
quantifiable, exceeding approximately 1 mg/m3 only occasionally 
(< 10% measurable).  

    Vinylidene chloride concentrations in the 1.640-4.08 µg/m3 
(0.35-1.02 ppb) range were measured at urban sites in New Jersey as 
part of the Airborne Trace Element and Organic Substances (ATEOS) 
project [68, 69].  However, the authors considered that the 
relatively high concentrations of vinylidene chloride found may be 
an artifact of 1,1,1-trichloroethane dehydrochlorination on the 
particular adsorption traps (Tenax GC) used in the study.  US EPA 
[225] estimated the ambient airborne level of vinylidene chloride 
to be 8.7 µg/m3and 20 ng/m3 in industrial-source and non- 
industrial areas of the USA, respectively.  In the Federal Republic 
of Germany, vinylidene chloride is classed among a group of organic 
compounds, the total emission of which must not exceed a 
concentration of 20 mg/m3 at a mass flow of 0.1 kg/h or more [88].  
5.1.2.  Occupational exposure

    Industrial air concentrations of vinylidene chloride should be 
restricted.  Ott et al.  [166] reported peak air exposure levels as 
high as 7600 mg/m3 in a polymer production plant with operators 
being exposed to estimated 8-h time-weighted average (TWA) 
concentrations of between < 20 and 280 mg/m3.  In a more recent 
survey in the USA [225], levels of vinylidene chloride in monomer 
and polymer plants were reported of 90-100 µg/m3 and 25-50 µg/m3, 
respectively.  Thus, exposures are generally within the time-
weighted average threshold limit value (TLVR) of 20 mg/m3 (5 ppm), 
recommended by the ACGIH (Table 5).  Similarly, vinylidene chloride 
levels in air in other manufacturing plants [91, 111,165] where 
exposure to vinylidene chloride was involved have been reported to 
be below 40 mg/m3.  This was also the case for occupational 
exposures in confined atmospheres (submarines and spacecraft) [1] 
and in certain USA telephone offices [155] where the airborne 
levels of vinylidene chloride were found not to exceed 8 mg/m3 and 
256 µg/m3, respectively.  

    Some national occupational exposure limits are listed in 
Table 5.  
5.2.  Water

    Vinylidene chloride has been measured in raw and treated 
effluents discharged from various industrial plants in the USA 
[225].  The mean levels detected in raw waste water in the USA 
ranged from 18 to 760 µg/litre.  Vinylidene chloride (isomer not 
specified) has been detected in effluent discharged from chemical 
manufacturing plants in the Netherlands at a concentration of 
32 µg/litre [47].  Going & Spigarelli [62] reported water levels at 
plant sites ranging from non-detectable to 550 µg/litre, the 
highest level being detected in an industrial waste water canal.  
Vinylidene chloride has also been detected in well and river water 
from various areas in the USA [200].  Discharge into a sewer is 
not an acceptable method of disposal for vinylidene chloride.  
Waste water is therefore injected with steam to allow the 
vaporization and recovery of vinylidene chloride.  Determination of 
the amount of vinylidene chloride in treated waste water [225] 
indicated that treatment effected a removal of between 40 and 97%.  

    In urban storm-water runoff samples in the USA, Cole et al.  
[30] reported a frequency of detection of vinylidene chloride of 
3% when determined among other priority pollutants.  The range 
of detected concentrations was 1.5-4 µg/litre.  

    Wegman et al., [242] investigated the level of vinylidene 
chloride present in water from 4 sampling sites in or around a 
chemical dump that had been used, in particular, for the disposal 
of by-products from a pesticide production plant.  The levels 
detected ranged from < 0.01 to 2.8 µg/litre, which compared with 
levels of 0.3-80 µg/litre reported by the authors to have been 
detected in the river Rhine.  

    Concentrations of up to 180 µg/litre were found in ground 
water beneath a major landfill site in Ottawa, Canada [121].  
Low levels of vinylidene chloride have also been observed in other 
selected contaminated ground waters in Ontario, Canada (Lesage, 
personal communication, Environment Canada).  

    Lake Ontario receives the largest burden of industrial and 
municipal effluents in the Great Lakes Basin with the highly 
polluted Niagara river contributing 80% of its total inflow.  
Water samples from 95 stations in Lake Ontario were analysed for a 
suite of volatile hydrocarbons [104].  Quantifiable amounts of 
vinylidene chloride were found at 4 stations in the lake (80-190 
ng/litre) and a relatively high value of 3500 ng/litre at the 
fifth station.  

    In the USSR, the maximum allowable concentration (MAC) of 
vinylidene chloride in surface water is 0.6 µg/litre [88].  

    In the study by Lao et al.  [115], grab samples of raw sewage 
and effluents from a sewage treatment plant were found to contain 
only trace levels of vinylidene chloride (not more than 1 
µg/litre).  In the same study, ground water from the vicinity 
of an abandoned waste dump contained a vinylidene chloride 
(isomer not stated) concentration of 138 µg/litre.  The levels of 
vinylidene chloride in drinking-water were generally non- 
detectable, the highest detected level being 0.06 µg/litre.  

Table 5.  Some occupational air exposure limits used in various countriesa
Country/          Exposure limit descriptionb                 Value    Effective
Organization                                                  (mg/m3)  datec
Belgium           Threshold limit value (TLV)                          1987 (r)
                  - Time-weighted average (TWA)               20
                  - Short-term exposure limit (STEL)          80

Brazil            Acceptable limit (AC) (48 h/week)           31       1982 (r)

Finland           Time-weighted average (TWA)                 40       Not given
                  - Short-term exposure limit (STEL)          80

Germany, Federal  Maximum work-site concentration (MAK)                1987 (r)
Republic of       - Time-weighted average (TWA)               8
                  - Short-term exposure limit (STEL 30 min)   16

Netherlands       Maximum limit (MXL)                                  1987 (r)
                  - Time-weighted average (TWA)               40
                  (notice of intended change)                 20

Poland            Maximum permissible concentration (MPC)              1985 (r)
                  - Ceiling value (CLV)                       50

Romania           Maximum permissible concentration (MPC)              1985 (r)
                  - Time-weighted average (TWA)               500
                  - Ceiling value (CLV)                       700

Sweden            Threshold limit value (TLV)                          1985
                  - Time-weighted average (TWA)               20
                  - Short-term exposure limit (STEL)          40
Switzerland       Maximum work-site concentration (MAK)                1987 (r)
                  - Time-weighted average (TWA)               8

United Kingdom    Recommended limit (RECL)                             1987 (r)
                  - Time-weighted average (TWA)               40
USA (ACGIH)       Permissible exposure limit (PEL)                     1987 (r)
                  - Time-weighted average (TWA)               20
                  - Short-term exposure limit (STEL)          80

Table 5.  (contd.)
Country/          Exposure limit descriptionb                 Value    Effective
Organization                                                  (mg/m3)  datec

USA (NIOSH)       Recommended exposure limit (REL)            lowest   1987 (r)

USSR              Maximum allowable concentration (MAC)                1977
                  - Ceiling value (CLV)                       50
a  From: IRPTC [88].
b  TWA =  A maximum mean exposure limit based generally over the period of a 
   working day (generally 8 or 12 h, except 15 min (Finland) and 30 min (FRG).
   STEL = A maximum concentration of exposure for a specified time duration 
   (generally 15 or 30 min).
c  When no effective date appears in the IRPTC legal file, the year of the reference 
   from which the data are taken is indicated by (r).

    Levels of vinylidene chloride in tap water from 
Philadelphia and Miami, USA were reported to be 0.1 µg/litre or 
less [47].  Vinylidene chloride levels were also < 1 µg/litre in 
raw water supplies at 30 potable water treatment facilities in 
Canada [163, 164].  In treated water, vinylidene chloride was 
detected in 1/30 supplies at an average concentration of < 1 
µg/litre.  The maximum concentration detected in potable water was 
20 µg/litre.  In the study by Wallace et al., [235] discussed in 
section 5.1.1, drinking-water samples were also analysed for 
vinylidene chloride.  The median coefficient of variance for 
analyses was < 10%.  Vinylidene chloride was detected 
occasionally; the percentage of samples that showed measurable 
concentrations was 26-43 (New Jersey), 10 (North Carolina), and 0 
(North Dakota).  The mean concentration in New Jersey drinking-
water was measured as 0.1 or 0.2 µg/litre, depending on the year of 
sampling, and did not exceed 2.5 µg/litre.  

    Otson [161] reported that vinylidene chloride was 
detectable in treated (but not untreated) water in only one out of 
ten municipal water supplies in the lower Great Lakes area of 
Canada.  At this one site, the concentration of vinylidene 
chloride in treated water was < 0.1 µg/litre.  Daily exposure 
of individuals via the drinking-water in the USA has been 
estimated at < 0.01 µg, though the maximum could exceed 1 µg 
[225].  The World Health Organization recommends a maximum 
concentration of 0.3 µg/litre of drinking-water [88].  The US EPA 
has proposed a Maximum Contaminant Level (MCL) for vinylidene 
chloride in drinking-water of 28 µg/litre (7 ppb) [42].  

    Trace levels of 2 commonly used solvents (trichloroethylene 
and tetrachloroethylene) have been found in the marine and 
freshwater environment [104,130, 231] as well as in ground water.  

There is an indication that vinylidene chloride may be produced in 
the degradation of these particular compounds [167, 174], but 
insufficient data are available to assess the overall importance 
of trichloroethylene and tetrachloroethylene as sources of 
vinylidene chloride in the environment.  

5.3.  Soil

    Contamination of the soil may arise through municipal solid 
waste disposal.  It has been estimated that, in the USA, the 
maximum level of total monomer in the soil does not exceed 81.7 kg 
(180 pounds) per year [150].  DeLeon et al.  [37] investigated the 
levels of vinylidene chloride in samples from 100 waste-disposal 
sites.  Only one out of three samples from a single site contained 
a detectable level of vinylidene chloride (21.9 mg/kg dry weight 
of soil).  All remaining samples contained < 10 mg/kg (not 

5.4.  Food and Food Packaging

    Food may be contaminated by the migration of residual 
vinylidene chloride monomer from packaging materials containing 
vinylidene chloride co-polymers.  
    A number of authors have measured residual levels of vinylidene 
chloride in commercial food packaging films.  A survey of food 
packaging materials carried out in 1975 in the United Kingdom 
indicated levels of residual monomer ranging from < 0.001 to 3.8 
mg/m2 [135].  The same group reported residual levels ranging from 
0.0003 to 0.4 mg/m2 from a survey for the period 1977-78.  Gilbert 
et al., [60] reported concentrations of vinylidene chloride 
monomer ranging from non-detectable (< 0.001 mg/m2) to 0.022 
mg/m2 in packaging films used for retail foods.  Going & 
Spigarelli [62] reported 4.9 to 58 mg vinylidene chloride/kg 
(4.9 and 58 ppm) in two samples of Saran wrap while Birkel et al.  
[18] reported levels of 6.5-26.2 mg/kg (6.5-26.2 ppm).  In a study 
by Hollifield & McNeal [78], vinylidene chloride monomer was 
detected in commercial food packaging films at 1.68.1 mg/kg.  
However, Tan & Okada [218] and Motegi et al.  [144] did not 
detect vinylidene chloride (< 1 mg/kg) in polyvinylidene chloride 
film used for fish jelly products, fish sausage, processed cheese, 
or in household wraps.  
    Levels of vinylidene chloride reported to migrate into food 
or food simulants have been quite low.  This is consistent with 
the high barrier properties of vinylidene chloride co-polymers.  
These co-polymers require little or no added plasticizers to 
produce flexible films.  This has an important effect on their 
migration characteristics since added plasticizers reduce the 
barrier properties of polymers.  As with any migrant, the amount 
of vinylidene chloride migration from food packaging depends on 
the duration of contact,  the temperature,  and the  original 
concentration in the polymer [142, 170].  

    Levels of vinylidene chloride were non-detectable (< 5 µg/kg, 
i.e., < 0.005 ppm) in a range of film packaged foodstuffs 
except for certain cooked meat products in which the maximum 
observed concentration was 10 µg/kg (0.001 ppm) [60].  Levels 
reported for a variety of foods packaged in vinylidene chloride-
containing materials ranged from < 1 to 6 µg/kg [135].  
    Studies on the migration into food simulants carried out by 
Dow [41] did not show any vinylidene chloride migrating from a 
vinylidene chloride/vinyl chloride co-polymer film into water (1 h; 
212 °F-detection limit 7.5 µg/kg, 7.5 ppb) or into peanut oil (1 h; 
212 °F-detection limit 2.5 µg/kg, 2.5 ppb).  Migration into 
heptane (a very efficient extraction solvent) was 13 µg/kg (13 ppb) 
after 1 h at 180 °F (from a film containing 12 mg residual 
monomer/kg).  A vinylidene chloride/methyl acrylate co-polymer 
containing residual vinylidene chloride at 9 mg/kg (9 ppm)  was 
extracted with cooking oil at 250 °F for 2 h and then at 120 °F for 
15 days.  The amount of vinylidene chloride measured in the oil was 
18 µg/kg (18 ppb).  Extraction with water under the same 
conditions resulted in 6 µg/litre (6 ppb) migration.  

    Gas chromatographic determination of sorption isotherms of 
vinylidene chloride on vinylidene chloride co-polymers by 
Demertzis et al.  [38] was consistent with a strong thermodynamic 
polymer monomer interaction leading to a low level of monomer 
migration from a polymeric package into a food-contacting medium.  

    It has been estimated that, in the United Kingdom, the 
maximum possible intake of vinylidene chloride from food as a 
result of the use of packaging materials is no more than 1 
µg/person per day [135].  

    Proposals for controls on the presence of vinylidene 
chloride in food-contact materials in the EEC seek to restrict 
residual vinylidene chloride levels to 5 mg/kg maximum in packaging 
material and to impose a maximum limit of 50 µg/kg on vinylidene 
chloride in foods [25].  There is currently no formal regulatory 
limit on residual vinylidene chloride monomer in food packaging in 
the USA.  The current major USA producer of Saran(R) has a quality 
control limit for residual vinylidene chloride in their food 
packaging film of 10 mg/kg (10 ppm) [41].  

    Aquatic organisms are a further possible source of 
contaminated foods.  While methods have been developed for analysis 
of fish tissue [44, 76], no reports of studies on vinylidene 
chloride levels in fish could be found.  However,  Ferrario et al.  
[48] have measured the concentration of vinylidene chloride in 
biota samples from three passes of Lake Pontchartrain, USA, which 
serve as a source of aquatic food for human consumption.  
Vinylidene chloride was not detected in oysters from the Inner 
Harbour Navigation Canal nor in clams from the Chef Menteur Pass.  
Clams from the Rigolets Pass contained vinylidene chloride at a 
concentration of 4.4 µg/kg wet weight.  


6.1.  Animals

6.1.1.  Absorption

    Vinylidene chloride has been shown to be well absorbed via the 
respiratory and oral routes in mammals.  No data are available on 
dermal absorption. Inhalation exposure 

    Uptake through inhalation in anaesthetized adult male Sprague-
Dawley rats was very rapid, substantial levels being found in 
venous blood within 2 min of exposure [35].  In this study, 
calculations of the amount of vinylidene chloride taken up in the 
body revealed that the cumulative uptake and metabolism of the 
inhaled chemical was linear for exposures ranging from 100 to 600 
mg/m3 (25 to 150 ppm).  There was a trend towards the establishment 
of equilibrium with saturation of metabolism in the rats exposed to 
1200 mg/m3 (300 ppm), evidenced by levels of vinylidene chloride in 
the blood and breath, which rose progressively during the last hour 
of the 3-h exposure.  This is in agreement with the approximate 
saturation of metabolism occurring at the inhalation concentration 
of 600 mg/m3 (150 ppm) that Filser & Bolt [49] determined by 
indirect measurement of vinylidene chloride uptake in male Wistar 
rats.  Andersen et al.  [6] found that uptake of vinylidene chloride 
from a closed chamber occurred in two phases in starved male 
Holtzmann rats.  The rate constant (2.2/h) of the initial rapid 
phase was independent of initial concentration (40-8000 mg/m3; 
10-2000 ppm) and appeared to represent tissue distribution.  
Metabolism became non-linear as dose levels increased (800-4000 
mg/m3; 200-1000 ppm), which is consistent with the findings of 
Dallas et al.  [35] and Filser & Bolt [49] mentioned above. Oral exposure 

    Jones & Hathaway [102] demonstrated that vinylidene chloride 
given intragastrically (0.5-350 mg/kg) was completely absorbed 
from the gastrointestinal tract of Alderley Park (Wistar-derived) 
male rats.  Peak arterial blood levels of orally administered 
vinylidene chloride (50 mg/kg) were observed within 8 min in male 
Sprague-Dawley rats [175] and the dose was completely absorbed.  
Complete absorption of an oral dose of 200 mg/kg to male Sprague-
Dawley rats was independent of dose vehicle (aqueous Tween 80, 
corn oil, or mineral oil) [27].  The vehicle did not affect the 
half-time for the initial rapid phase of exhalation of vinylidene 
chloride but the later half-time values were dependent on the 
rates of absorption, which decreased according to the vehicle in 
the following order (Tween 80 >corn oil >mineral oil).  

6.1.2.  Distribution and storage

    Whole-body autoradiography revealed that an intragastric 
dose of [14C]-vinylidene chloride administered to 80-g Alderley 

Park strain male rats was distributed throughout the tissues of the 
body within 1 h after initial concentration of the radiolabel in 
the liver and kidneys, which retained 14C for the longest times 
after dosing [102].  McKenna et al.  [133] also studied the tissue 
distribution of [14C]-vinylidene chloride following oral dosing 
(1 or 50 mg/kg) in male Sprague-Dawley rats.  Tissue residues, 72 h 
after dosing, were found in descending order in the liver, kidneys, 
and other tissues including lung, muscle, skin, blood, and fat.  

    Similarly, 14C activity derived from inhaled [14C]-vinylidene 
chloride (exposure concentrations of 40 or 800 mg/m3 (10 or 200 
ppm) for 6 h) in fed male Sprague-Dawley rats (4 animals per group) 
was also highest in the liver and kidneys, 72 h after termination 
of exposure.  The levels in other tissues at this time showed the 
following trend: lung >skin >plasma >carcass >muscle and fat 

6.1.3.  Elimination

    The elimination of vinylidene chloride administered 
intravenously (10-100 mg/kg in 50% polyethylene glycol 400) to fed 
and fasted male Sprague-Dawley rats followed a tri-exponential 
pattern corresponding to different half-times and redistribution 
among tissue compartments.  The biological half-life ranged from 
approximately 4045 min (10 mg/kg iv) to approximately 55-70 min 
(100 mg/kg iv).  In orally dosed animals, the half-life values were 
significantly reduced by fasting suggesting delayed absorption in 
fed animals [175]. Elimination of unchanged vinylidene chloride 

    As the capacity for the metabolism of vinylidene chloride is 
subject to saturation (section 6.1.4), the pulmonary elimination 
of unchanged vinylidene chloride is dose dependent.  Male rats 
given an oral dose of 1 mg/kg, excreted <3% of the dose unchanged 
via the lung [133].  A similar finding that only 1% of an oral dose 
(0.5 mg/kg) to rats was eliminated via the pulmonary route was 
reported by Jones & Hathaway [102].  However, at higher oral dose 
levels, for example at 350 mg/kg, nearly 70% of the dose was 
eliminated unchanged via the lungs within 72 h [102].  In a 
separate study, almost 50% of an oral dose of 200 mg/kg was 
eliminated via the lungs in rats [27].  The non-linear dose 
dependency of pulmonary elimination following oral administration, 
in addition to being influenced by saturable metabolism, is also 
determined by an efficient transfer of vinylidene chloride from the 
arteries to the alveoli.  Thus, 80% of an intravenous dose of 0.5 
mg/kg was eliminated unchanged via the lungs in 1 h.  Hence, 
vinylidene chloride that escapes first pass hepatic metabolism is 
largely removed by pulmonary excretion [102].  Very similar results 
were obtained by Reichert et al.  [184] using female rats.  In this 
study, 1.3, 9.7, or 16.5% of the dose was exhaled within 72 h as 
unchanged vinylidene chloride after single oral doses of 0.5, 5, or 
50 mg/kg, respectively.  Fasting of rats for 18 h prior to 
vinylidene chloride administration (50 mg/kg, oral) led to a 
reduction in metabolism and consequently a higher level of exhaled 
unchanged compound [133].  

    The biphasic pulmonary elimination of [14C]-vinylidene chloride 
in rats displayed half-lives of 21 and 66 min at an oral dose of 50 
mg/kg and approximately 25 and 117 min at an oral dose of 1 mg/kg 
[133].  When an oral dose of 200 mg/kg was administered to 
Sprague-Dawley rats, the half-life values for the initial rapid 
phase ranged from 15 to 21 min and from 10 to 13 min for fasted and 
fed rats, respectively.  The later slow phase of vinylidene 
chloride exhalation was most prolonged when the compound was 
administered in mineral oil (respective half-life values of 257 and 
280 min), intermediate when it was given in corn oil (73 and 103 
min), and shortest (22 and 42 min) when the vehicle was aqueous 
Tween-80 [27].  Following inhalation of 40 mg [14C]-vinylidene 
chloride/m3 (10 ppm), the biphasic pulmonary elimination in rats 
displayed half-life values of 20 and 217 min for the rapid and slow 
phases, respectively [132].  As with the oral route, rats exposed to 
a relatively high dose (800 mg/m3; 200 ppm) excreted a greater 
percentage (fed rats 4.7% and fasted rats 8.3%) of their body 
burden via the lungs than rats exposed to a low exposure of 40 
mg/m3 (10 ppm) (fed rats 1.63% and fasted rats 1.60%).  The 
pharmacokinetics of orally dosed and inhaled vinylidene chloride in 
fed and fasted rats are illustrated in Fig.  1. Elimination of metabolites 

    In the studies reported above [ 102, 133], in which fed rats 
were dosed orally with 0.5 or 1 mg [14C]-vinylidene chloride/kg, 
the major route of excretion of metabolites was the urine (63-80% 
of dose in 3 days).  In bile duct-cannulated rats, urinary 
excretion of 14C was markedly reduced by approximately the same 
extent as biliary 14C secretion [102].  Hence, approximately half of 
the urinary metabolites appeared to be derived from the bile 
following enterohepatic circulation.  The lungs were a minor route 
of elimination of metabolites, 5-14% of the dose was exhaled as 
carbon dioxide (CO2).  Urine was also the major excretory route 
for vinylidene chloride metabolites in mice following oral 
administration [103], only 8-16% of the dose appearing as 
metabolites in the faeces.  This was also the case following 
intraperitoneal administration.  At a higher oral dose level (350 
mg/kg), as expected from the saturation of metabolism, a lower 
level of approximately 30% of the dose appeared as urinary 
metabolites with less than 1% as CO2 in expired air and 1.3% in the 
faeces [102].  Following an intermediate oral dose of 50 mg/kg 
[133], urinary and faecal elimination were 47% and 4%, 
respectively, with only 4% exhaled as CO2.  Urinary elimination was 
biphasic at oral doses of 1 and 50 mg/kg and the initial rapid and 
terminal phases of urinary elimination displayed half-lives of 
approximately 6 and 17 h, respectively [133].  Results in female 
rats were similar to those in males in that 43.6, 53.9, and 42.1% 
of the dose appeared in the urine following oral administration of 
0.5, 5, and 50 mg/kg [14C]-vinylidene chloride, respectively.  The 
respective values for CO2 in expired air were 13.6, 11.4, and 6.1% 
[184].  Female rats also eliminated metabolites via the faeces 
(15.7, 14.5, and 7.7% of the dose, respectively), presumably via 
the biliary route.  


  Following inhalation of [14C]-vinylidene chloride [132] at 40 
mg/m3 (10 ppm), fed rats excreted 75% of the body burden as urinary 
metabolites, 8.7% as CO2 from the lungs, and 9.7% in the faeces.  At 
800 mg/m3 (200 ppm), these percentages were slightly lower because 
a greater proportion of the dose was expired unchanged.  

    In conclusion, irrespective of the route of administration, 
the urine is the major route of excretion of metabolites of 
vinylidene chloride.  The extent of elimination by the urine is 
dependent on dose, since a larger proportion of the dose is 
eliminated unchanged via the lung at relatively high dose levels, 
because of the saturation of the metabolism.  The efficiency of 
elimination is such that vinylidene chloride is not expected to 
accumulate in animals.  

6.1.4.  Metabolic transformation

    The profile of metabolites of vinylidene chloride produced in 
rats is shown in Fig.  2.  This pathway is based on the study by 
Jones & Hathaway [102] with supportive and, in some cases, 
conflicting or additional data superimposed.  The proportion of 
vinylidene chloride that is not eliminated unchanged in exhaled air 
undergoes initial oxidation catalysed by the cytochrome P-450 

system.  The postulated transient product of this reaction, 
vinylidene chloride oxide, has escaped isolation because of its 
instability.  This intermediate may be directly conjugated with 
glutathione or, following an intramolecular rearrangement, 
conjugated with mono- or bis-glutathione or with phosphatidyl 
ethanolamine.  Monochloroacetic acid may also be formed by 
hydrolysis and this may be conjugated with glutathione and further 
metabolized via a pathway involving beta-thionase activity or 
alternatively may be degraded to CO2 via glycolic and oxalic acids.  


    In the study by Jones & Hathaway [102], the metabolic fate of 
[14C]-vinylidene chloride was investigated in groups of 4 Alderley 
Park (Wistar derived) male rats.  Excreta were analysed for 
radiolabel following a single intragastric dose of either [1-14C]- 
or [2-14C]-vinylidene chloride (350 mg/kg).  Urinary metabolites 
were separated by gas chromatography and mass spectra were obtained 
for major metabolites.  The metabolic fate of a single oral dose of 
[14C]-vinylidene chloride was studied in female Wistar rats by 
Reichert et al.  [184], who also used gas chromatography and mass 
spectroscopy for the identification of metabolites.  The results 
confirmed the thiodiglycolic acid pathway (Fig.  2) reported by 
Jones & Hathaway [102].  However, these authors were unable to 
detect any hydroxyethyl mercapturic acid (Fig.  2), which McKenna et 
al.  [133] had proposed to be a metabolite in male Sprague-Dawley 
rats on the basis of analysis of the methylated product by mass 

spectroscopy.  A metabolic pathway involving phosphatidyl 
ethanolamine was uncovered by Reichert et al.  [184] by the 
isolation of the ethanolamine derivative of chloroacetic acid (12% 
of urinary 14C) (Fig.  2).  While this derivative may stem from the 
reaction of phosphatidyl ethanolamine with chloroacetic acid 
chloride, it has been proposed by Costa & Ivanetich [32] (see 
below) that the reaction may be with dichloroacetaldehyde (Fig.  2).  

    The metabolic fate of vinylidene chloride (50 mg/kg, oral) in 
Alderley Park male mice is qualitatively very similar to that 
described for the rat [103].  An exception is the excretion by the 
mouse (but not the rat) of a small amount of  N- acetyl- S- (2-
carboxymethyl) cysteine, derived either from the  N- acetyl- S- 
cysteinyl acetyl derivative or from  S- (carboxymethyl) cysteine, 
which are common to both species.  Quantitative differences between 
the metabolites formed in the two species are shown in Table 6.  It 
is seen that mice metabolized 22% more of the administered dose 
than rats and, consequently, released less unchanged vinylidene 
chloride in the expired air.  The species difference was attributed 
to higher cytochrome P-450-mediated epoxidation in mice.  The 
quantitative difference in the proportion of the  N- acetyl- S- 
cysteinyl acetyl derivative correlates with that expected on the 
basis of hepatic glutathione- S- epoxide transferase activity in 
these species, and may also be influenced by the lower extent of 
chloroacetic acid metabolism in mice.  Exposure to 40 mg [14C]-
vinylidene chloride/m3 (10 ppm) for 6 h resulted in a body burden 
of 5.3 mg equivalents/kg in male Ha (ICR) mice compared with 2.9 
mg equivalents/kg in male Sprague-Dawley rats [131].  Since only 
0.65 and 1.63% of the dose were recovered respectively, as 
unchanged vinylidene chloride, it was concluded that total 
metabolism was more efficient in the mouse, as reported by Jones & 
Hathaway [103].  

Table 6.  Relative proportion of 14C excretory products 
after oral administration of [1-14C]-vinylidene chloride 
to rodents at 50 mg/kga
[14C] Excretory products         % of 14C dose
                                 Mice  Rats
 Pulmonary excretion
Unchanged vinylidene chloride    6     28 
CO2                              3     3.5
 Urinary excretion
Chloroacetic acid                0     1
Thiodiglycollic acid             3     22
Thioglycollic acid               5     3
Dithioglycollic acid             23    5
Thioglycollyloxalic acid         3     2
 N-Acetyl- S-cysteinyl 
 acetyl derivative               50    28
 N-Acetyl- S-(2-carboxymethyl)
 cysteine                        4
Urea                             3     3.5
a  From: Jones & Hathway [103].

    Recent studies by Liebler & Guengerich [122] confirmed the 
hydrolytic lability of vinylidene chloride oxide, which was 
chemically synthesized and characterized by nuclear magnetic 
resonance and mass spectroscopy.  Selectivity was observed 
between purified rat liver cytochrome P-450s in the production of 
Cl2CHCHO and P-450 inactivation but not in glycolic acid 
(ClCH2CO2H) production.  Further, aqueous decomposition of 
vinylidene chloride did not produce Cl2CHCHO and yielded glycolic 
acid only at low pH.  These data, coupled with kinetic studies of 
vinylidene chloride oxidation, suggest that vinylidene chloride 
oxide is not an obligate intermediate in Cl2CHCHO and ClCH2CO2H 
production.  A proposed scheme for the role of cytochrome P-450 is 
shown in Fig.  3.  Whether or not this scheme operates  in vivo , is 


    The role of cytochrome P-450 in the metabolism of vinylidene 
chloride was confirmed by the measurement of a Type I difference 
spectrum with the bound substrate in hepatic microsomes from male 
Long-Evans rats [32].  Addition of vinylidene chloride to 
microsomes also stimulated carbon monoxide-inhibitable NADPH 
oxidation.  NADPH was required for the conversion of vinylidene 
chloride to monochloroacetic acid and dichloroacetaldehyde (not 
found in the  in vivo studies reported above), and these 
metabolites were not formed in the presence of cytochrome P-450 
inhibitors SKF-525A and carbon monoxide.  Pretreatment of rats with 

the cytochrome P-450-inducing agent beta-naphthoflavone did not 
elevate the hepatic microsomal metabolism of vinylidene chloride, 
and the cytochrome P-450-inducing agent phenobarbital gave a 
slight enhancement of metabolism per mg microsomal protein.  More 
noticeable was the marked enhancement of the ability of liver 
preparations to produce mutagenic metabolites of vinylidene 
chloride  in vitro following treatment of female BD-VI rats with the 
selective inducing agents phenobarbital and 3-methylcholanthrene 

    In a study by Sato et al.  [195], male Wistar rats were given 
ethanol in the diet (2% ethanol, increased by 1% daily to a final 
concentration of 5%, equivalent to 30% of total calorie intake).  
Hepatic microsomes derived from the ethanol-treated rats 
metabolized vinylidene chloride at a rate of 100.6 nmol/g liver per 
min compared with 31.1 nmol/g liver per min in control rat 
microsomes, indicating induction of microsomal enzymes involved in 
vinylidene chloride metabolism.  

    As shown in Fig.  2, conjugation with glutathione required 
prior microsomal metabolism of vinylidene chloride [131].  The 
importance of glutathione in vinylidene chloride metabolism was 
studied by Andersen et al.  [7].  Pretreatment of rats with agents 
that deplete hepatic non-protein sulfhydryl concentrations caused a 
marked inhibition of vinylidene chloride metabolism as measured by 
gas uptake (which is determined by metabolism).  In particular, 
treatment with cyclohexene oxide and dimethylmaleate resulted in 
76 and 54% inhibition, respectively.  Reichert et al.  [183] also 
noted an 18% reduction in the metabolism of vinylidene chloride 
(given as 20 000 mg/m3 (5000 ppm) in the gaseous phase) in 
isolated perfused rat livers following diethylmaleate 
administration.  This was considered to be due to an 85% reduction 
in glutathione levels.  The finding that the glutathione conjugate 
ClCH2COSG is able to  S- alkylate a second glutathione molecule to 
yield GSCH2COSG [123, 124] suggests that the monoglutathione 
conjugate may have the ability to interact with proteins, such as 
those involved in the transport of glutathione conjugates.  

    The rate of metabolism of vinylidene chloride by isolated 
hepatocytes from phenobarbital-pretreated male Long-Evans rats was 
studied by Costa & Ivanetich [33] using the maximum dose of 
vinylidene chloride that was not cytotoxic (2.1 mmol vinylidene 
chloride/litre).  The metabolites detected were dichloroacetic 
acid (0.15 nmol/106 cells per 10 min), monochloroacetic acid 
(0.068 nmol/106 cells per 60 min), and dichloroethanol (0.01 
nmol/106 cells per 10 min).  2-Chloroethanol and 
chloroacetaldehyde were not detected (<12 and <4 nmol/106 cells 
per 30 min, respectively).  No attempt was made to hydrolyse 

    In summary, the phase I metabolism of vinylidene chloride in 
rodents involves the action of cytochrome P-450 and the production 
of monochloroacetic acid.  This, and its precursors, may undergo 
conjugation with glutathione and/or phosphatidyl ethanolamine 
prior to further conversions.  Metabolism in the mouse occurs at a 
greater rate than in the rat and results in a similar metabolic 

profile with a relatively higher proportion of glutathione 
conjugate derivatives.  
6.1.5.  Reaction with cellular macromolecules

    The specific interaction of vinylidene chloride metabolite(s) 
with DNA is covered in section 8.5.1.  

    In the studies by McKenna et al.  [132, 133] reported in section, fasted rats showed a reduced capacity to metabolize 
relatively high doses of both orally administered and inhaled 
[14C]-vinylidene chloride.  Fasted rats exposed to 800 mg 
vinylidene chloride/m3 (200 ppm) sustained liver and kidney 
damage, which was not found in fed rats.  This toxicity was 
associated with a greater level of covalently bound radiolabel in 
the liver of the fasted animals.  An elevated level of covalent 
binding in the liver was also seen as a result of depriving rats of 
food prior to administration of an oral dose of 50 mg vinylidene 
chloride/kg.  The results can be explained by the binding of 
reactive metabolites (presumed to be vinylidene chloride oxide 
and/or chloroacetyl chloride) to nucleophilic sites in tissue 
macromolecules.  This is thought to be enhanced by the depletion of 
glutathione during fasting [93], which operates as an alternative 
nucleophile [131].  Following exposure of male rats to 20800 mg 
[14C]-vinylidene chloride/m3 (5200 ppm) for 6 h [131], hepatic non-
protein sulfhydryl levels fell in a dose-dependent saturable 
manner.  Appreciable covalent binding of radiolabel to hepatic 
protein occurred when 30% or more glutathione was depleted.  
Covalent binding of radiolabel to hepatic and kidney tissue in mice 
occurred at the rate of 22 and 80-µg equivalents/g protein, 
respectively, compared with 5 and 13 µg equivalents/g protein, 
respectively, in rat tissue following exposure to 40 mg [14C]-
vinylidene chloride/m3 (10 ppm)for 6 h.  

    In a separate study on rats by Reichert et al.  [183], the rate 
of depletion of glutathione after oral doses of vinylidene chloride 
was also found to be exponentially dependent on the concentration.  
However, the authors questioned the correlation between a low 
glutathione level and relatively high toxicity in fasted rats, 
since the fall in glutathione levels after oral administration of 
vinylidene chloride (1000 mg/kg) was identical in fasted rats and 
fed rats.  Furthermore, the rate of metabolism of vinylidene 
chloride by isolated perfused livers (20 000 mg vinylidene 
chloride/m3 (5000 ppm) in the gaseous phase) was not affected by an 
18-h fast.  The interpretation of these data is difficult in the 
light of other results reported in this section.  

    Jaeger et al.  [93] reported a diurnal variation in the levels 
of glutathione in male Holtzmann rats.  The animals were most 
sensitive to the lethal and hepatotoxic effects of vinylidene 
chloride when glutathione levels were at a minimum.  Jaeger et 
al.  [96] also correlated susceptibility to the hepatotoxicity 
of vinylidene chloride (exposure for 4 h at 4000 mg/m3 (1000 ppm)) 
to decreased hepatic glutathione concentrations in male Holtzmann 
rats that had been fasted for 18 h or had been treated with 

diethylmaleate.  In a further study [97], the hepatic glutathione 
concentration was decreased by the administration of 
trichloropropane epoxide (0.1 ml of a 10% solution/kg) to fasted 
rats.  This treatment was also associated with elevated toxicity of 
vinylidene chloride.  A qualitative, but not a quantitative, 
difference in the metabolism of vinylidene chloride (8000 mg/m3 
(2000 ppm) initial exposure) resulted from the fasting of rats.  
Thirty minutes after exposure to [14C]-vinylidene chloride at the 
same concentration, the radioactivity in liver mitochondria and 
microsomes was largely TCA-insoluble and was greater in fasted than 
in control rats.  Judging from the turn-over time of TCA-insoluble 
14C, it was suggested that this 14C had entered the metabolic pool 
rather than being covalently bound to macromolecules.  However, 
the demonstration of labile thiol adducts [123] could explain this 
    Covalent binding of [1,2-14C]-vinylidene chloride to tissues 
peaked 6 h after an intraperitoneal dose of 125 mg/kg in male 
C57B1/6N mice [159].  Pretreatment with diethylmaleate, which 
depletes glutathione, enhanced covalent binding in the liver, 
lung, and kidney, and also enhanced lethal toxicity.  In accordance 
with evidence for the formation of reactive metabolites of 
vinylidene chloride by cytochrome P-450, covalent binding was 
increased in liver and lung tissue by pretreatment with the  P-450  
inducers,  phenobarbital and 3-methylcholanthrene.  Inhibitors 
of cytochrome P-450, piperonyl butoxide, and SKF-525A all decreased 
covalent binding in the liver and lung.  However, binding to kidney 
tissue was not affected by P-450-inducing agents, was decreased by 
piperonyl butoxide and was increased by SKF-525A.  Covalent binding 
occurred in hepatic and lung microsomes from these mice following 
incubation of microsomes with NADPH.  Surprisingly, however, oxygen 
did not appear to be necessary.  Kidney microsomes could not 
metabolize vinylidene chloride to products that covalently bound to 
tissue macromolecules, unless the mice had been pretreated with 
cytochrome P-450-inducing agents suggesting that, in the absence 
of enzyme induction, covalent binding in the kidney  in vivo was 
mediated by hepatic metabolites [157, 158].  Covalent binding of 
[14C]-vinylidene chloride to lung and liver tissue accompanied 
bronchiolar necrosis in CD-1 mice given an intraperitoneal dose 
(125 mg/kg); only mild hepatic necrosis was observed ([56]section  The effects of various inducers and inhibitors of 
cytochrome P-450 activity on toxicity and covalent binding were 
variable in line with the evidence for microsomal-mediated 
activation and deactivation (section 8.1.2) and in accordance 
with multiple reactive metabolites (see below).  Vinylidene chloride 
epoxide, 2-chloroacetyl chloride, 2,2-dichloro-acetaldehyde, 2-
chloroacetic acid and  S- (2-chloroacetyl)-glutathione all bind 
covalently to thiols  in vitro [123, 124].  Covalent binding of 
radiolabel to microsomal protein occurred following incubation of 
[14C]-vinylidene chloride with rat and human liver microsomes.  When 
rat microsomes were used, binding was inhibited by alcohol 
dehydrogenase + NADH, suggesting that 2,2-dichloroacetaldehyde 
played a role in the binding process.  Metabolites of [14C]-
vinylidene chloride bound to microsomes from isolated lung as 
well as from the liver of CD-1 mice [54].  By the use of specific 
inhibitors and agents that induce cytochrome P-450 isoenzymes, 

these authors were able to demonstrate the role of cytochrome P-450 
isoenzymes in the production of reactive metabolites, though some 
non-specific covalent binding was also seen.  

    In summary, there are a number of reactive metabolites of 
vinylidene chloride, the production of which is dependent on the 
activity of cytochrome P-450.  In rodents, each of these products 
may contribute to the depletion of glutathione and to covalent 
binding to tissue macromolecules, which is greater in the liver 
than in the kidney.  The greater covalent binding of reactive 
metabolites to tissue macromolecules in the mouse compared with the 
rat is correlated with a relatively higher rate of metabolism 
(section 6.1.4) and higher toxicity (section  

6.1.6.  Transformation by non-mammalian species

    No data were available to the Task Group on vinylidene chloride 
metabolism in non-mammalian species, other than bacteria.  
6.2.  Human Beings

    No data have been reported on the kinetics and metabolism of 
vinylidene chloride in human beings, other than some very limited 
information obtained indirectly through the following studies.  
Liver 9000-g supernatants (S9) from four adults, who did not show 
any pathological lesions, were capable of catalysing the formation 
of products that were mutagenic to  Salmonella typhimurium [15] 
(section 8.5.2), suggesting that human cytochrome P-450 can 
metabolize vinylidene chloride.  The rate of conversion of 
vinylidene chloride to dichloroacetaldehyde in hepatic microsomes 
from two human organ donors (one of each sex) was 0.0340-0.038 
nmol/min per nmol cytochrome P-450.  The conversion was shown (by 
lack of significant antibody inhibition) not to be mediated by 
debrisoquine hydroxylase (a form of cytochrome P-450, which is 
polymorphic in human beings) [245].  This rate of microsomal 
metabolism to dichloroacetaldehyde is similar to that reported by 
Costa & Ivanetich [33] for the rat (0.028 nmol dichloroacetaldehyde 
and 0.035 nmol chloroacetate produced/min per nmol cytochrome 

    Vinylidene chloride is exhaled in human breath following 
inhalation exposure [233].  Breath from student volunteers, in 
Texas and North Carolina, USA, was sampled using a spirometer as 
the subjects inhaled pure air.  The ratio of vinylidene chloride in 
the breath to that in pre-exposure air was 0.78 ± 0.86 (n = 15).  A 
significant Spearman correlation coefficient of 0.77 was determined 
between air and breath levels of vinylidene chloride in 17 human 
subjects.  The following log-linear model was capable of giving a 
reasonable prediction of breath levels from the preceding 8-h air 
exposure levels: log concentration in breath (µg/m3) = 0.24 ± 0.67 
+ (0.71 ± 0.17) log concentration in air (µg/m3).  The authors 
suggested that, if these observations were confirmed, recent 
exposures and body burdens of individuals could be estimated from 
breath analysis.  However, this may be hampered by biphasic 
elimination as reported for animals (section 6.1.3).  

7.1.  Effects on the Stratospheric Ozone Layer

   The rapid destruction of vinylidene chloride in the troposphere 
by hydroxyl radicals (section 4.1.1) indicates that the substance 
is unlikely to participate in the depletion of the stratospheric 
ozone layer.  

7.2.  Aquatic Organisms

    Studies on the impact of vinylidene chloride on living 
organisms have concentrated on the aquatic environment and include 
discussions on the levels of vinylidene chloride detected (section 

    According to Leblanc [117], the acute toxicity for the water 
flea ( Daphnia magna), under static conditions, is of a similar 
magnitude to that reported by Buccafusco et al.  [21] for the 
bluegill fish (see below).  The median LC50 values were 98 mg/litre 
(95% confidence interval; range, 71-130 mg/litre) and 79 mg/litre 
(95% confidence interval; range, 61-110 mg/litre) for 24 h and 48 
h, respectively.  The "no discernible effect" level for the water 
flea was less than 2.4 mg/litre.  

    Dawson et al.  [36] treated fresh-water bluegill sunfish 
( Lepomis macrochiras) and marine tidewater silverside fish 
( Menidia beryllina) with vinylidene chloride (132-750 mg/litre 
and 180-320 mg/litre, respectively) for up to 96 h under static 
conditions.  No attempt was made to prevent loss of vinylidene 
chloride by evaporation.  The best-fit median lethal concentrations 
(LC50) for 96 h were 220 and 250 mg/litre for bluegill sunfish and 
tidewater silverside fish, respectively.  Since these values were 
less than 500 mg/litre (500 ppm), vinylidene chloride was 
designated a hazardous substance.  The 96-h static LC50 of 
vinylidene chloride in juvenile marine sheepshead minnows 
( Cyprinodon variegatus) was very similar to the above values (250 
mg/litre; range, 200-340 mg/litre, 95% confidence limits), and was 
the same when measured at 24 h [72].  The no-observed-effect 
concentration was 80 mg/litre.  The acute toxicity in bluegill fish 
( L.  macrochirus) was also investigated by Buccafusco et al.  [2] 
under static conditions, in capped jars to minimize volatilization.  
The recorded LC50 value was 74 mg/litre (95% confidence interval, 
57-91 mg/litre) at 96 h.  This LC50, which was identical at 24 h, 
is somewhat lower than those reported in the studies by Dawson et 
al.  [36] and Heitmuller et al.  [72].  Toxicity values similar to 
those noted above for fish and  Daphnia were reported in a review by 
Atri [9].  

    The assays under static uncapped conditions reported here are 
relevant to acute spill conditions.  One-week flow-through studies 
have also been carried out by Dill et al.  [39].  The LC50 value for 
fathead minnows ( Pimephales  promelas Rafinesque) in flowing water 
was 29 mg/litre (range, 23-34 mg/litre) after 7 days exposure, 
whereas the 96-h LC50 was 108 mg/litre (range, 85-117 mg/litre) 

under flow-through conditions.  Swimming disorientation was 
observed to be the major sublethal toxic effect of vinylidene 
chloride.  A bioconcentration factor of 4 and a bioaccumulation 
factor of 6.9 have been reported for fish in a review by Atri [9].  

    Few data are available on the sublethal effects of vinylidene 
chloride on aquatic organisms.  Preliminary studies demonstrated 
that hepatic neoplastic lesions were not produced in guppy 
( Poecilia reticulata) and Japanese medaka ( Oryzias latipes) 
exposed to vinylidene chloride concentrations of up to 40 mg/litre 
(40 ppm) for 3 months [71] (personal communication, Hawkins Gulf 
Coast Research Laboratory, Mississippi, USA).  

8.1.  Single Exposures

    Acute toxicity data (LC50s and LD50s) for common laboratory 
animals are shown in Table 7.  
8.1.1.  Inhalation Rats 

    In an early study by Carpenter et al.  [24], 3 groups of 6 
Sherman rats were exposed to vinylidene chloride vapour for 4 h at 
various concentrations.  Within a 14-day post-exposure observation 
period, a concentration of 128 000 mg/m3 (32 000 ppm) was lethal 
for 2/6, 3/6, and 4/6 animals, respectively.  Later, Siegel et al.  
[206] estimated a 4-h LC50 of 25 400 mg vinylidene chloride/m3 
(6350 ppm) for groups of 16 male Sprague-Dawley-derived rats.  

    Siletchnik & Carlson [211] considered that lethality from 
vinylidene chloride might be related to cardiotoxicity.  They 
exposed male Charles River albino rats to 102 400 mg vinylidene 
chloride/m3 (25 600 ppm) for 10 min or more and noted progressive 
sinus bradycardia and arrhythmias (AV-block), multiple 
continuous ventricular contractions, and ventricular fibrillation.  
This treatment with vinylidene chloride also produced a marked 
increase in sensitivity to epinephrine-induced cardiac arrhythmias.  
Phenobarbital pretreatment enhanced the cardiac-sensitizing 
properties of vinylidene chloride.  

    However, Jaeger et al.  [95] reported that death from vinylidene 
chloride inhalation was associated with bloody ascites in all 
animals, with no signs of cardiac failure, and was therefore 
thought to be due to vascular collapse and shock.  

    In the studies by Zeller et al.  [248, 249], the estimated 
LC50s of vinylidene chloride (Table 7) were lowered by fasting in 
both male and female Sprague-Dawley rats.  Females were less 
susceptible than males to the lethal effect.  Post-mortem 
examination of animals dying from vinylidene chloride exposure 
revealed acute contraction of heart blood vessels, acute swellings 
and localized bloody oedema in the lung, greyish enlarged liver 
lobules, and pale kidneys.  Ascites and hydrothorax were also seen.  

Table 7.  Acute toxicity of vinylidene chloride for laboratory animals
Species Sex    Nutri-       Estimated LC50/LD50         Dosing criteria    Limit of     Reference
               tional                                                      observation
               status                                                      time
______________________________________________________________________________________________________                                                                                      statustion time
Rat     male,  fed          approximately 128 000 mg/m3 Inhalation, 4 h    14 days      [24]
        female              (32 000 ppm)

Rat     male   fed          25 400 mg/m3 (6350 ppm)     Inhalation, 4 h    14 days      [206]
Rat     male   fed          60 000 mg/m3 (15 000 ppm)   Inhalation, 4 h    24 h         [96]

Rat     male   fed          approximately 8000 mg/m3    inhalation, 4 h    23 h         [93]
                            (2000 ppm)                  (pm but not am)

Rat     male   fed          28 400 mg/m3 (7100 ppm)     Inhalation, 4 h    14 days      [249]

Rat     male   18-h fasted  2400 mg/m3 (600 ppm)        Inhalation, 4 h    24 h         [96]

Rat     male   fasted       not measurable because of   inhalation, 4 h                 [5]
               (overnight)  non-linear concentration-
                            mortality relationship

Rat     male   16-h fasted  1660 mg/m3 (415 ppm)        Inhalation, 4 h    14 days      [248]

Rat     female fed          41 200 mg/m3 (10 300 ppm)   Inhalation, 4 h    14 days      [249]

Rat     female 16-h fasted  26 260 mg/m3 (6565 ppm)     Inhalation, 4 h    14 days      [248]

Mouse   male   fed          392 mg/m3 (98 ppm)          inhalation, 1 day               [204]
        female              420 mg/m3 (105 ppm)

Mouse   male   fed          140 mg/m3 (35 ppm)          Inhalation, 2 days              [204]

Mouse   male   fed          460 mg/m3 (115 ppm)         Inhalation, 4 h    14 days      [251]

Mouse   male   fasted       200 mg/m3 (50 ppm)          Inhalation, 4 h    14 days      [250]
Mouse   female fed          820 mg/m3 (205 ppm)         Inhalation, 4 h    14 days      [251]

Mouse   female fasted       500 mg/m3 (125 ppm)         Inhalation, 4 h    14 days      [250]

Table 7.  (contd.)
Species Sex    Nutri-       Estimated LC50/LD50         Dosing criteria    Limit of     Reference
               tional                                                      observation
               status                                                      time
______________________________________________________________________________________________________                                                                                      statustion time
Hamster male   fed          6640 mg/m3(1660 ppm)        Inhalation, 4 h    14 days      [109]
Hamster male   fasted       600 mg/m3 (150 ppm)         Inhalation, 4 h    14 days      [108]
Hamster female fed          11 780 mg/m3 (2945 ppm)     Inhalation, 4 h    14 days      [109] 

Hamster female fasted       1780 mg/m3 (445 ppm)        Inhalation, 4 h    14 days      [108]
Rat     male   fed          1550 mg/kg                  gavage             24 h         [100]

Rat     male   fed          1510 mg/kg                  gavage             96 h         [100]

Rat     male   fed          1800 mg/kg                  gavage             not stated   [172]
Rat     female fed          1500 mg/kg                  gavage             not stated   [172] 

Rat     male   fed          800-2000 mg/kg              gavage             14 days      [2]
Mouse   male   fed          201-235 mg/kg               gavage             not stated   [103] 

Mouse   female fed          171-221 mg/kg               gavage             not stated   [103]
a  This report noted that mortality was consistently observed at doses as low as 50 mg/kg.  In 73-g 
   male rats, dose-mortality curves showed a maximum mortality (10/10) at 300 mg/kg.  Percent 
   mortality then decreased as dose was increased to 800 mg/kg.

    Jaeger et al.  [96] showed that the toxicity of vinylidene 
chloride in male Holtzman rats was enhanced as a result of fasting.
The estimated 24-h LC50 for fed rats was 60 000 mg/m3 (15 000
ppm) (4-h exposure), while the corresponding value for 18-h fasted
rats was 2400 mg/m3 (600 ppm) (n = 5 or 6).  The minimum lethal 
concentrations were 40 000 and 800 mg/m3 (10 000 and 200 ppm), 
respectively.  At levels of 600 mg/m3 (150 ppm) or more, serum-
alanine-alpha-ketoglutarate transaminase rose rapidly in fasted 
rats (within 2 h of termination of a 4-h exposure at 8000 mg/m3 
(2000 ppm)).  This indication of liver damage did not arise at 
levels below 8000 mg/m3 (2000 ppm) in rats provided with food.  
The increased susceptibility of fasted rats was considered to be 
due to decreased availability of hepatic glutathione and this was 
supported by the potentiation of hepatotoxicity by treatment of 
fed rats with the agent diethylmaleate, which depletes glutathione
(section 6.1.5).  This was further supported by the observation 
[93] that a 4-h exposure of male Holtzman rats to 8000 mg
vinylidene chloride/m3 (2000 ppm) in the morning produced a
3-fold increase in serum alanine-alpha-ketoglutarate transaminase
activity with no deaths.  Conversely, the same treatment in the
afternoon resulted in an almost 10-fold increase in serum
alanine-alpha-ketoglutarate transaminase, and 2 out of 5 treated
rats died within 23 h.  The relative susceptibilities were
inversely related to hepatic glutathione levels.  

    In fasted male Sprague-Dawley rats exposed to 800 mg vinylidene 
chloride/m3 (0.02%) , liver toxicity was observed within 2 h 
[188].  Toxicity in liver parenchyma was characterized by 
retraction of cell borders and the formation of pericellular 
"lacunae".  Nuclei showed segregation of chromatin towards the 
margins of the nuclear envelope and mitochondria were swollen with 
ruptured outer membranes.  Midzonal hepatic necrosis led to 
haemorrhagic centrilobular necrosis within 6 h.  This liver 
necrosis, along with raised levels of serum-alanine-alpha-
ketoglutarate transaminase and an associated fall in hepatic 
glutathione levels, were all minimized by pretreatment of rats 
with the cytochrome P-450-inducing agents phenobarbital and 

    In an earlier study [23], male Sprague-Dawley rats were exposed 
to 5760 mg vinylidene chloride/m3 (1440 ppm) for 1 h.  Twenty-four 
hours later, liver damage was detected by measured elevations in 
serum glutamic oxalacetic transaminase and glutamic pyruvic 
transaminase.  Pretreatment of these animals with phenobarbital and 
3-methylcholanthrene did not alter the extent of the elevation of 
serum hepatic enzyme levels.  Furthermore, the activity of glucose-
6-phosphatase in the liver was also unaffected 24 h after exposure 
to 9080 or 11 960 mg vinylidene chloride/m3 (2270 ppm or 2990 ppm) 
in both 3-methylcholanthrene and phenobarbital-treated animals.  
In contrast, exposure to 80 000 or 130 000 mg vinylidene 
chloride/m3 (20 000 or 32 500 ppm) for 1 h was lethal for most of 
the rats (groups of 4 rats) pretreated with the inducing agents, 
despite the fact that these concentrations did not produce 
deaths in similar groups of control rats.  Treatment of rats with 
the cytochrome P-450 inhibitors "SKF-525A" and "Lilly 18947" reduced 

the survival time after inhalation of 168 000 or 212 000 mg 
vinylidene chloride/m3 (42 000 ppm or 53 000 ppm).  Because of the 
differential effects of inducing agents on hepatotoxicity and 
lethality, the results suggest that the lethal effects of inhaled 
vinylidene chloride are distinct from the hepatotoxic effects.  
Since cytochrome P-450 has been implicated in the activation of 
vinylidene chloride to form toxic metabolite(s) (section 6.1.4) the 
protective or lack of potentiating effect of inducing agents on 
hepatotoxicity is not understood, but may result from multiple 
roles of microsomal enzymes (section  

    Subsequently, Reynolds et al.  [189] exposed fasted male rats 
to 800 mg vinylidene chloride/m3 (200 ppm).  Glutathione levels in 
the liver were rapidly depleted during the first and second hours 
of exposure and were replenished during the third and fourth hours, 
when toxicity was determined by analysis of tissue sections by 
light microscopy.  The rebound of glutathione levels was not 
observed in the mitochondria, which might indicate a role of this 
organelle in toxicity.  Inactivation of the microsomal enzyme 
cytochrome P-450 was not appreciable prior to histological 
alterations in the liver and therefore did not appear to be an 
early event in cytotoxicity.  The toxicity of vinylidene chloride 
(2000 or 4000 mg/m3 (500 or 1000 ppm)) inhaled for 3 or 24 h was 
exacerbated by the glutathione-depleting agent phorone, as 
evidenced by an increase in the levels of serum-aminotransferases 
and sorbitol dehydrogenase at 3 h and mortality at 24 h in male 
Wistar rats [207].  Phorone (250 mg/kg) also had the effect of 
increasing the half-life of the terminal elimination phase of 
vinylidene chloride from 0.89 to 2.33 h and from 1.55 to 4.21 h at 
levels of 2000 and 4000 mg vinylidene chloride/m3 (500 and 1000 
ppm), respectively, in a closed exposure chamber.  Therefore, 
increased toxicity was associated with decreased metabolism.  
Since there was no evidence for an effect of phorone on the 
activity of the mixed-function oxidase, the authors proposed that 
phorone produced a quantitative change in vinylidene chloride 
metabolism leading to intermediates of greater toxicity.  However, 
the results might also be explained by a build up of intermediates 
(due to reduced ability to conjugate with glutathione) that inhibit 
their own formation.  

    Andersen et al.  [5] studied the dependence of inhalation 
toxicity (as measured by plasma aspartate transaminase) on both 
exposure concentration and duration in fasted male HOT:SD(BR) 
Holtzman rats.  Plasma-enzyme levels increased markedly after 
exposure to 800 mg vinylidene chloride/m3 (200 ppm) for 1.25 h.  
After this time, no further increase in plasma aspartate 
transaminase was recorded.  The concentrationmortality curve 
increased rapidly between 400 and 800 mg/m3 (100-200 ppm) and 
reached a plateau between 800 and 4000 mg/m3 (200-1000 ppm), making 
it impossible to make a meaningful estimate of the LC50.  Thus, a 
concentration x time relationship for toxicity is not apparent, 
and this is in agreement with saturable metabolism (section to toxic intermediates.  Thus, estimates by other workers 
of the LC50 under similar conditions cannot be considered accurate.  

    After inhalation of 800 mg vinylidene chloride/m3 (200 ppm) 
for 0.5 h, immature rats showed significant prolongation of 
pentobarbital-induced sleeping times, suggesting an inhibition of 
pentobarbital metabolism [5].  This increase in sleeping times was 
maintained for at least 3 days after a 2-h exposure.  In mature 
rats, treated with 1600 mg/m3 (400 ppm) for 2 h, there was no 
evidence of an altered sleeping time within the exposure period, 
though this was elevated 2 and 24 h later.  

    Exposure of fasted male rats to 8000 mg vinylidene chloride/m3 
(2000 ppm) for 4 h led not only to elevation of serum alanine 
alpha-ketoglutarate transaminase levels but also to increased 
levels of hepatic sodium and calcium with a concomitant decrease in 
potassium and magnesium levels and diminished histochemical 
glucose-6-phosphatase activity.  These changes were associated 
with centrilobular necrosis and haemorrhagic necrosis of the entire 
hepatic lobule.  Thyroidectomized, fasted rats, exposed under the 
same conditions, showed significantly less change in hepatic 
electrolyte concentrations.  Morphological injury was also 
minimized and was similar to that seen in non-pretreated fed 
animals.  Mortality was also inhibited by thyroidectomy.  In 
contrast, thyroxine pretreatment potentiated the toxicity of 
vinylidene chloride and restored the susceptibility of 
thyroidectomized rats.  It was suggested that the protective 
effect of thyroidectomy was at least partially mediated by the 
observed elevation of hepatic glutathione levels [216].  

    However, differences were observed between fed, fasted, and 
hyperthyroid Sprague-Dawley rats in the effects of orally 
administered vinylidene chloride (50 mg/kg body weight) on body 
temperature, serum glucose concentrations, hepatic glutathione, 
and glutathione transferase [106].  The different patterns of 
response in the three groups suggest different mechanisms of 
toxicity in fasted and hyperthyroid rats.  

    Similar findings were reported by Jaeger et al.  [98].  In a 
study on male Sprague-Dawley rats, a raised serum sorbitol 
dehydrogenase level (a cytoplasmic marker) coincided with an 
elevation in serum ornithine carbamoyl transaminase from the 
mitochondria.  This finding suggests that mitochondrial damage is an 
early event in the hepatotoxicity of vinylidene chloride.  The data 
support the authors' theory that the metabolite monochloracetic 
acid is toxic to mitochondria via chlorocitric acid and "lethal 
synthesis" leading to accumulation of citric acid [97].  

    The kidney is also affected by vinylidene chloride.  At 
sublethal concentrations (800 mg/m3 (200 ppm) for 6 h), male 
Sprague-Dawley rats given food  ad libitum did not show any signs of 
an adverse response [132].  In contrast, rats previously fasted for 
18 h, were found to have haemoglobinuria, which persisted for 12-
24 h after exposure.  As well as seeing multiple foci of hepatic 
centrilobular degeneration and necrosis, marked degeneration 
of kidney proximal tubular epithelia was observed after this 
exposure in the fasted rats, but not in those that were fed.  These 
changes were associated with an increase in the level of 14C 

covalently bound in the liver following exposure to [14C]-
vinylidene chloride (section 6.1.5).  Hepatotoxic effects were not 
noted in either fed or fasted rats exposed to 40 mg vinylidene 
chloride/m3 (10 ppm).  In a more recent study, inhalation of 
vinylidene chloride produced acute nephrotoxicity (which was not 
associated with calcium oxalate formation) in male Sprague-Dawley 
rats [90].  Twenty-four hours after a 4-h exposure to 1000 mg 
vinylidene chloride/m3 (250 ppm) or more, kidney/body weight 
ratios, serum urea nitrogen, and creatinine levels were 
significantly increased.  This was associated with moderate 
cellular swelling in the renal cortex (800 mg/m3 (200 ppm)) and 
severe tubular necrosis (>1200 mg/m3 (>300 ppm)).  Aroclor-1254 
and phenobarbital pretreatment antagonized renal toxicity. Mice 

    A marked individual variation in the lethal concentration 
of vinylidene chloride (ranging from 500 to 10 000 mg/m3; 125 to 
2500 ppm) was noted by Lazarev [116].  

    In the study by Short et al.  [204], the toxicity of inhaled 
vinylidene chloride was investigated in CD-1 mice.  The 1- and 2-day 
LC50 values for groups of 10 mice were approximately 400 mg/m3 (100 
ppm) (males and females) and 140 mg/m3 (35 ppm) (males), 
respectively.  These values are considerably lower than those 
reported for rats and, in contrast to the data on mice, no deaths 
were seen in male rats exposed to 240 mg vinylidene chloride/m3 
(60 ppm).  In addition, up to 240 mg vinylidene chloride/m3 (60 
ppm) produced a dose-dependent histopathological change in mouse 
liver and an increase in both serum glutamic oxaloacetic 
transaminase and serum glutamic pyruvic transaminase.  The serum 
enzymes were also elevated in male rats but not to the same extent 
and only with a longer exposure period.  Mice exposed for 1 day to 
60 mg vinylidene chloride/m3 (15 ppm) showed hepatocellular 
degeneration and increased mitotic figures of hepatocytes together 
with severe kidney tubular nephrosis.  At 120 mg/m3 (30 ppm), 
midzonal hepatic necrosis was also seen, the severity of which was 
increased at 240 mg/m3 (60 ppm).  In contrast, rats exposed to 240 
mg/m3 (60 ppm) for 1 day showed only mild hepatic centrilobular 
degeneration and/or necrosis and mild bileduct hyperplasia.  The 
inhibition of these toxic effects and of covalent binding of 
[14C]-vinylidene chloride-derived radioactivity in the mouse liver 
and kidney by disulfiram was described.  The mechanism of this 
protection was not established but may be via modulation of 

    The studies of Zeller et al.  [250] on NMRI mice showed that, 
as with rats, males were more susceptible than females (Table 7) 
and that fasting potentiated lethality.  Symptoms included apathy, 
narcosis, dyspnoea, and immobility.  Postmortem examination of 
mice dying from vinylidene chloride exposure particularly showed 
acute emphysema and congestion of lungs.  

    The effects of vinylidene chloride on DNA following acute 
inhalation (40 or 200 mg/m3 (10 or 50 ppm) for 6 h) have been 
studied in male CD-1 mice as well as Sprague-Dawley rats [186].  
These exposures gave rise to tissue damage (nephrosis, increased 
mitotic figures, and regeneration) and increased DNA semi-
conservative replication (25-fold) in mouse kidney, but not in 
mouse liver.  In contrast, DNA semiconservative replication in rat 
kidney was increased only 2.2 fold and was slightly decreased in 
rat liver following exposure to 40 mg/m3 (10 ppm).  DNA repair and 
DNA alkylation in these organs were minimal in both rats and mice 
(section 8.5.1).  In the light of these minimal effects, the 
authors suggested that the carcinogenicity of vinylidene chloride 
in the mouse kidney (section 8.7.1) might be via an epigenetic 
mechanism. Other animal species 

    Effects of vinylidene chloride on the respiratory system have 
also been reported in cats, rabbits, and guinea-pigs [192].  
Pulmonary irritation and lung oedema, haemorrhage, and pneumonia 
were seen following exposure to vinylidene chloride at 2000 or 6000 
mg/m3 (500 or 1500 ppm) (cats) and 5000 or 8000 mg/m3 (1250 or 2000 
ppm) (guinea-pigs) for 2 h.  Exposure to concentrations ranging from 
500 to 2000 mg/m3 (125 to 500 ppm) for 40 min inhibited spinal 
reflexes in rabbits.  This species survived after exposure for 40 
min to a concentration of 30 000 mg/m3 (7500 ppm).  Klimisch & 
Freisberg [108, 109] studied the inhalation toxicity of vinylidene 
chloride in fed and fasted Chinese striped hamsters.  The LC50 
values are given in Table 7.  As with rats and mice, males were 
more susceptible to lethality than females, and fasting potentiated 
the toxicity markedly.  Hamsters that died showed acute dilation 
and passive hyperaemia of the heart, congested lungs, and 
lobulation of the liver.  

8.1.2.  Oral

    As with inhalation, the principal organs affected by oral 
administration of vinylidene chloride are the liver, kidneys, and 

    The LD50 values for orally administered vinylidene chloride in 
rats and mice are shown in Table 7.  It can again be seen that mice 
are more susceptible than rats, but few sex differences in response 
are observed following administration of vinylidene chloride by 
gavage. Rats 

    Hepatic damage produced by intubation of 400 mg vinylidene 
chloride/kg to fasted rats was indicated by elevation of serum 
alanine alpha-ketoglutarate transaminase activity within 4 h [94].  
The level of glucose-6-phosphatase activity was reduced in the 
liver at 8 h, but not after 4 h, suggesting (in line with the 
above discussion) that initial toxicity was not associated with the 
endoplasmic reticulum membrane.  Treatment of rats with a 

relatively high dose of 12.5 mmol vinylidene chloride/kg did not 
lead to elevation of malondialdehyde or conjugated dienes in 
incubated liver homogenates taken 1 h after dosing.  This 
contrasts with the effect of a hepatotoxic dose of carbon 
tetrachloride and suggests that lipid peroxidation is not involved 
in the hepatotoxicity of vinylidene chloride.  

    Jenkins et al.  [100] also reported, that pretreatment of rats 
with the microsomal enzyme-inducing agent phenobarbital offered 
protection against the hepatotoxic effects of orally administered 
vinylidene chloride.  The acute 24-h toxicity of vinylidene 
chloride was enhanced 18-fold by adrenalectomy, suggesting that the 
adrenals were involved in protection against lethal effects.  The 
mechanisms of protection were not understood.  

    The effects of induction and inhibition of microsomal enzymes 
in fasted male Holtzman rats were studied in more detail by 
Andersen et al.  [4].  Pretreatment of rats with phenobarbital 
markedly reduced the lethality of a 100 mg/kg oral dose of 
vinylidene chloride in immature rats (140 g), but not in large 
adult (331 g) rats.  

    These results suggest that a microsomal detoxification system, 
inducible in immature rats, was operative.  This is supported by 
the finding that the cytochrome P-450 inhibitor SKF-525A 
exacerbated the lethal effects of a dose of vinylidene chloride of 
200 mg/kg in rats (260-270 g) but did not have any effect on 
mortality in immature (80-100 g) 2,3-epoxy-propan-1-ol, rats.  One 
of a range of epoxides that exacerbate the toxicity of orally 
administered vinylidene chloride, which is particularly potent, was 
a relatively poor substrate for glutathione- S- transferase and 
styrene oxide hydrolase.  Thus 2,3-epoxypropan-1-ol, rather than 
inhibiting the protective effects of epoxide hydrolase or 
glutathione conjugation (section 6.1.4) appeared to inhibit a 
further (uncharacterized) detoxification pathway [3].  The role of a 
further microsomal enzyme system in the production of a toxic 
intermediate was indicated by the protective effects of 
pretreatment of rats of all sizes with pyrazole, 3-aminotriazole, 
and carbon tetrachloride against the lethality of an oral dose of 
200 mg/kg [4].  

    Andersen & Jenkins [2] noted that female Holtzman HOT:(SD)BR 
rats were much less susceptible to the hepatotoxic effect than 
male rats, the threshold oral dose for the elevation of plasma 
transaminase activity being approximately 100 mg/kg in the females.  
When mature, male rats were given 400 mg vinylidene chloride/kg, 
levels of plasma-aspartate transaminase were 4-5 times greater in 
18-h fasted rats than in control rats.  The effects of fasting are 
thought to be due to glutathione depletion (section 6.1.5).  
Chieco et al.  [28] studied hepatotoxicity in fasted male 
Sprague-Dawley rats given vinylidene chloride as an oral dose in 
mineral oil.  Two hours after dosing with 200 mg vinylidene 
chloride/kg or 6 h after a lower dose of 50 mg/kg, early damage to 
plasma and mitochondrial membranes was indicated by raised hepatic 
sodium levels and decreased central area histochemical staining 

of bile canaliculi membrane Mg2+-ATPase, outer membrane 
mitochondrial monoamine oxidase, and inner membrane mitochondrial 
succinate dehydrogenase and cytochrome oxidase.  The extent of 
injury (indicated by raised serum transaminase activity and 
decreased histochemical staining of membrane components) increased 
with time after dosing or with increased dose.  Four and 6 h after 
administration of a 200 mg/kg dose, necrosis occurred around the 
central vein of the liver.  There were no histochemical alterations 
in the kidneys at 6 h.  The same investigators [27] noted that 
this treatment produced increased plasma-haemoglobin levels and 
granular haem casts in the loop of Henlé.  No pathological changes 
were seen in the heart, lungs, spleen, adrenals, or duodenum.  
Hepatic damage was more severe with Tween 80 used as a dose vehicle 
than with corn oil or mineral oil, reflecting a relatively high 
rate of absorption when administered in Tween 80 (section  

    Eight hours after oral administration of 40 mg vinylidene 
chloride/kg body weight to rats, centrilobular hepatocytes showed a 
dilated endoplasmic reticulum and swollen mitochondria and 
perinuclear cisternae.  The nucleosplasm was homogeneous suggesting 
chromatinolysis [5].  

    In unanaesthetized, freely moving fed and fasted Sprague-
Dawley male rats [148], at least a 2-fold increase in inulin 
excretion was observed within 2 h of oral administration of 200 mg 
vinylidene chloride/kg.  Bile flow decreased in treated rats (up to 
40% and 65% in the fed and fasted rats, respectively).  Thus, 
vinylidene chloride alters hepatobiliary permeability and causes 

    Kanz & Reynolds [105] investigated the occurrence of 
morphological changes in the liver in relation to time after oral 
administration of vinylidene chloride (25, 50, or 100 mg/kg in 
mineral oil) (see also Kanz et al.  [106], reported in section  One, 2, or 3 h after administration to fasted male 
Sprague-Dawley rats, the liver was examined microscopically 
following  in situ perfusion fixation.  Dilation of the bile 
canaliculi with an increase in the number of microvilli or membrane 
fragments in canaliculi was seen with the formation of canalicular 
diverticuli in centrilobular hepatocytes within 1-2 h.  
Subsequently, microvilli on the sinusoidal surfaces were lost, and 
cytoplasmic vacuolation occurred.  These early changes were seen 
without morphological alteration of the endoplasmic reticulum or 
mitochondria.  Not until 4-6 h after an oral dose of 200 mg 
vinylidene chloride/kg was a decrease seen in the activity of 
enzymes in the sinusoidal plasma, mitochondrial matrix, 
endoplasmic reticulum, lysosomes and cytosol, and then only in 
regions of gross injury.  At 2 h, scattered hepatocytes showed 
nuclear and cell surface anomalies that were characteristic of 
apoptosis [190].  

    In agreement with the findings of Reynolds et al.  [189] in 
inhalation studies (section, Moslen & Reynolds [147] found 
that loss of activity of microsomal cytochrome P-450 was not an 
early event in the toxicity of vinylidene chloride (200 mg/kg) 

orally administered to fasted male Sprague-Dawley rats.  
Cytochrome P-450 deactivation was concomitant with an elevation in 
the activities of serum glutamate oxalacetate transaminase and 
serum glutamate pyruvate transaminase and did not occur until 
between 2 and 3 h after administration of vinylidene chloride.  
These effects were preceded by a marked inhibition (within 1 h) of 
the activity of glutathione- S- transferase towards 
dichloronitrobenzene, chlorodinitrobenzene, and 1,2-epoxy-3-( p- 
nitrophenoxy)-propane (but not towards ethacrynic acid) and a 
concomitant reduction of hepatic glutathione levels.  A correlation 
was found between the dose-dependency of inhibition of 
glutathione- S- transferase activity and of cytotoxicity.  Thus, 
both glutathione depletion and inhibition of specific glutathione-
 S- transferase(s) precede toxicity.  

    Simultaneous treatment of 8 male Wistar rats with ethanol (4.8 
g/kg, oral) protected against the hepatotoxicity of vinylidene 
chloride (0.125 g/kg, oral) as measured by the elevation of the 
activities of serum aminotransferases and sorbitol dehydrogenase 
[208].  Conversely, pretreatment of rats with ethanol (5% in 
drinking-water for 7 days) exacerbated the hepatotoxicity of orally 
administered vinylidene chloride (0.125 or 0.2 g/kg).  Dithiocarb or 
(+)-catechin (0.2 g/kg) administered simultaneously with vinylidene 
chloride also reduced vinylidene chloride-induced hepatotoxicity.  
Evidence was provided that the simultaneous treatment with ethanol 
and dithiocarb may lead to depression of the metabolism of 
vinylidene chloride.  It was postulated that (+)-catechin might act 
as a scavenger of reactive intermediate(s), which may also be the 
mechanism of protection afforded by (+)-cyanidanol-3 [207].  

    Acetone is another agent that modifies the hepatotoxicity 
of orally administered vinylidene chloride [75].  Administration of 
5 or 10 mmol acetone/kg orally to male Sprague-Dawley rats 
potentiated liver injury (elevated plasma glutamic pyruvic 
transaminase and ornithine carbamyl transferase activity and liver 
total bilirubin content) caused by a single oral dose of 50 mg 
vinylidene chloride/kg.  However, acetone given at 1, 15, or 30 
mmol/kg, did not potentiate hepatotoxicity.  The biphasic effect 
of acetone could not be explained but was considered by the authors 
to be related to dose-dependent changes in more than one 
biotransformation process.  
    A further effect of vinylidene chloride was the prolongation of 
barbiturate sleeping times [92].  Two to 4 h after an oral dose of 
400 mg vinylidene chloride/kg to male Holtzman rats, the 
pentobarbital sleeping time was elevated (136% of control), (prior 
to hepatotoxicity as indicated by loss of glucose-6-phosphatase 
activity).  Both hexobarbital and pentobarbital sleeping times were 
elevated at 17-22 h, concomitant with hepatic injury.  The early 
effects on pentobarbital sleeping times were due, not to decreased 
metabolism of the barbiturate, but to an elevation of its 
concentration in serum through altered absorption or distribution.  

    Kidney toxicity was studied by Jenkins & Andersen [99] in 
NMRI:0(SD), Sprague-Dawley-derived rats.  Within 24 h of oral 
administration of 400 mg vinylidene chloride/kg , fasted male rats 
showed raised levels of plasma urea nitrogen and creatinine.  
Within 48 h, tubular dilation was observed with necrosis and 
vacuolation of tubular epithelium.  Some tubules contained a blue-
black amorphous material.  These histopathological effects were 
preceded by inflammation in some animals.  Elevation of plasma urea 
nitrogen and creatinine was not observed in fed rats with identical 
treatment and was less evident in fasted females than in males.  
However, the histopathological effects were no less severe in the 
female rats.  The time-course for the nephrotoxic response (maximum 
at 48 h) in male and female fasted rats was slightly preceded by 
hepatotoxicity as indicated by the appearance in the plasma of 
aspartate transaminase, alanine transaminase lactate dehydrogenase, 
and sorbitol dehydrogenase (maximum at 8-24 h).  This finding is 
in agreement with that reported above [28]. Mice 

    Orally administered vinylidene chloride also caused pulmonary 
injury in male C57B1/6 mice [52].  Following administration of 
100 mg/kg, peribronchial and perivascular oedema were seen 
in the lungs.  Histopathology revealed dilation of Clara cell 
cisternae and degeneration of the endoplasmic reticulum.  A 200 
mg/kg dose caused severe necrosis of ciliated and Clara cells and 
exfoliation of the bronchial lining within 6 h.  Both doses caused 
concurrent hepatotoxicity as evidenced by raised levels of serum 
glutamic oxalacetic transaminase and glutamic pyruvic transaminase.  
By 24 h, pulmonary oedema, haemorrhage, and focal atelectasis 
were also observed in association with hypoxia.  Recovery was seen 
within 7 days.  Following a higher dose of 200 mg/kg, injury was 
seen to be followed by cellular proliferation as indicated by 
incorporation of a pulse of [3H]-thymidine into total 
pulmonary DNA  [53].  Proliferative activity reached a peak 
between 3 and 5 days after treatment with vinylidene chloride.  
The majority of the 3H was incorporated into non-ciliated 
bronchiolar epithelial cells.  

8.1.3.  Other routes Intraperitoneal 

    When given by intraperitoneal (ip) injection to male ddY strain 
mice at a dose level of 120 mg/kg (0.1 ml/kg), vinylidene chloride 
produced hypothermia within 30 min and severe renal damage at 24 h 
(as shown by elevated plasma urea nitrogen and kidney calcium 
levels) [143].  Renal tubular necrosis was much more severe than 
hepatic damage.  Pretreatment of mice with diethyldithiocarbamate or 
carbon disulfide protected against renal and hepatic toxicity, 
possibly via an inhibitory effect on metabolic activation.  
Vinylidene chloride at 605 mg/kg (0.5 ml/kg, ip) caused liver 
damage in male Sprague-Dawley rats as evidenced by raised serum 
glutamate pyruvate transaminase and increased bile duct pancreatic 
fluid flow at 24 h [70].  Hepatic microsomal glucose-6-phosphatase 

and ATP-dependent calcium pump were both inhibited 24 h after 
intraperitoneal administration of vinylidene chloride (1 mg/kg) to 
male Sprague-Dawley rats [145].  The level of conjugated dienes in 
microsomes obtained 2 h after vinylidene chloride injection was 
not significantly different from that measured in control rat 
microsomes, suggesting that the toxic effects were not mediated by 
lipid peroxidation.  
    The results of Siegers et al.  [209] also suggest that lipid 
peroxidation is not a mechanism involved in the early stages of 
vinylidene chloride hepatotoxicity.  Up to 2 h after an 
intraperitoneal injection of 0.5 g vinylidene chloride/kg to male 
Wistar rats, ethane exhalation was only slightly higher than the 
control levels and was not affected by hypoxia.  

    As was observed in the short-term inhalation studies on 
vinylidene chloride (section 8.2.1), the compound was found to 
induce cytochrome P-450 activity following a single administration 
to C57B1/6N mice by intraperitoneal injection.  Over the range of 
50-150 mg/kg, a dose-dependent induction of microsomal 7-
ethoxyresorufin and 7-ethoxycoumarin  O- deethylation (but not total 
cytochrome P-450 content or benzo (alpha)pyrene hydroxylase) was found 
in the kidney [112].  

    Male C57BL/6J mice given 125 mg vinylidene chloride/kg (ip) 
developed extensive necrosis of the Clara cells in the lung within 
24 h, but no necrosis was observed in the liver or kidney at this 
time.  The loss of Clara cells was associated with a significant 
decrease in pulmonary cytochrome P-450 content and activity 
[113].  The susceptibility of the Clara cells was considered to be 
due to activation of vinylidene chloride by cytochrome P-450 in 
these cells.  This conclusion was also reached by Forkert et al.  
[55] who showed that covalent binding of vinylidene chloride 
products to cellular macromolecules in the lung accompanied lung 
toxicity in CD-1 mice given an identical dose to that given in the 
study described above (section 6.1.5).  Degenerative changes 
occurred in Clara cells as early as 1 h following treatment with 
vinylidene chloride and were characterized by mitochondrial 
swelling and aggregation of chromatin against the nuclear membrane.  
Cell death was apparent at 2 h and, by 24 h, the majority of Clara 
cells were exfoliated [56].  However, these authors concluded that 
there was a lack of correlation between the extent of covalent 
binding and either lung or liver toxicity [55]. Eyes and skin 

    Little information is available on the effects of vinylidene 
chloride on the eyes and skin.  

    It is moderately irritating to the eyes of rabbits causing 
transient corneal injury and is also a skin irritant in the rabbit 
[222].  Rylova, [192] reported that vinylidene chloride was an 
irritant for the eyes of rats, mice, guinea-pigs, and cats.  

    Transient redness was observed following application to shaved 
rabbit skin.  The stabilizer ( p- methoxyphenol) in vinylidene 
chloride preparations may contribute to irritation.  

8.1.4.  Summary of acute toxicity

    Vinylidene chloride may cause irritation of the skin and eye, 
depression of the central nervous system, and acute toxic effects 
on the heart, lung, liver, and kidney.  The variation in estimations 
of the acute LC50 for vinylidene chloride is considerable.  This 
can be explained partially by inaccuracies that arise because of a 
non-linear concentration-mortality relationship.  Generally, mice 
are more susceptible than rats and males are more susceptible than 
females.  The toxic effects are dependent on cytochrome P-450 
activity (which may also be involved in detoxification) and can be 
exacerbated by glutathione depletion.  Hepatotoxicity may be 
enhanced by ethanol and thyroxine, inhibited by dithiocarb and 
(+)- catechin, and modulated by acetone.  

8.2.  Short-Term Exposures

8.2.1.  Inhalation

    In the study by Prendergast et al.  [173], groups of various 
animal species were continuously or repeatedly exposed to 
vinylidene chloride through inhalation for 90 days.  The results 
are shown in Table 8.  In survivors of continuous exposure at a 
concentration of 101 mg/m3 or less, no histopathological changes 
could be attributed to vinylidene chloride.  At 189 mg/m3, livers 
from surviving dogs, monkeys, and rats showed morphological 
changes consisting of fatty metamorphosis, focal necrosis, 
haemosiderin deposition, lymphocytic infiltration, bile-duct 
proliferation, fibrosis, and pseudolobule formation, particularly 
in dogs.  All rats displayed nuclear hypertrophy of the kidney 
tubular epithelium.  Non-specific inflammatory changes were seen in 
the lungs of a majority of the animals.  Liver alkaline phosphatase 
activity and serum glutamic-pyruvic transaminase activity were 
measured in rats and guinea-pigs and found to be elevated.  Dogs, 
monkeys, and rats showed reduced weight gain.  The repeated 
exposures are considered to be more relevant to human 
occupational exposure.  Gross examination of survivors showed a 
high incidence of lung congestion in rabbits, monkeys, rats, and 
guinea-pigs.  Some fatty infiltration and several cases of focal and 
sub-massive necrosis were observed in guinea-pig liver sections.  

Table 8.  Mortality  of animals exposed to vinylidene chloride by inhalationa
                                       Mortality ratiob
Concentration  Extent of  Rat (Long  Guinea-   Rabbit   Beagle  Squirrel
of vinylidene  exposurec  Evans or   pig       (New     dog     monkey
chloride                  Sprague-   (Hartley) Zealand
(mg/m3)                   Dawley)              White)
395 ± 32       A          0/15       0/15      0/3      0/2     0/3
189 ± 6.2      B          0/15       7/15      -        0/2     3/9

101 ± 4.4      B          0/15       3/15      0/3      0/2     2/3

61 ± 5.7       B          0/15       3/15      -        0/2     0/9
20 ± 2.1       B          2/45       2/45      -        0/6     1/21

no treatment   B          7/304      2/314     2/48     0/34    1/57
a  From: Prendergast et al.  [173].
b  Mortality ratio shows the number of animals that died divided by the 
   number with which the study commenced.
c  A = 30 exposures, 8 h/day, 5 days/week.
   B = continuous 90-day exposure.

    Shortly after this study, Gage [57] investigated the toxicity 
of vinylidene chloride in Alderley Park rats.  In this case, groups 
of 4 male and 4 female rats were exposed to 2000 mg vinylidene 
chloride/m3 (500 ppm) for 6 h per day over a period of 20 days.  
Nose irritation and retarded weight gain were observed, and, at 
autopsy, liver cell degeneration was detected by histology.  At 800 
mg/m3 (200 ppm) (4 male and 4 female rats), slight nose 
irritation was seen, but the organs were normal on autopsy.  

    Inhalation studies [152, 176] demonstrated minimal recoverable
liver cell cytoplasmic vacuolation in Sprague-Dawley rats (20 
animals per sex) after 90 days exposure for 6 h per day, 5 
days/week, to vinylidene chloride at 100 or 300 mg/m3 (25 or 75 
ppm).  At both dose levels, body weight, haematology, urinalyses, 
blood urea nitrogen, serum alkaline phosphatase and glutamic 
pyruvic transaminase activities, gross pathology, organ weights,
kidneys, heart, testes, and brain were normal.  

    Maltoni & Patella [138] noted a greater toxicity in rats than 
that reported by Gage [57].  The effects of 4 h exposure, 4-5 days 
per week, for 28 days, were studied in Sprague-Dawley rats and 
Swiss mice (40-800 mg/m3 (10-200 ppm)), Balb/c, C3H, and C57B1 mice 
(600-800 mg/m3 (150-200 ppm)), and Chinese hamsters (100 mg/m3 (25 
ppm) only).  The exposure periods were reduced at or above 200 
mg/m3 (50 ppm) in mice because of severe acute toxicity, and the 
800 mg/m3 (200 ppm) treatment of rats was reduced to 600 mg/m3 (150 
ppm) after 2 days because of toxic effects.  A minimum of 30 
animals was used in all groups exposed to vinylidene chloride.  

    The weight of animals, clinical signs of toxicity, mortality, 
and histopathological changes were monitored at, or up to, 28 days, 
except in the case of mice exposed to 400-800 mg/m3 (100-200 ppm), 
when the observation period was 9 days.  Histopathological studies 
indicated that the liver and kidneys were the major target organs.  
The toxicity varied with animal species and strain, susceptibility 
being in the following order: Swiss mice >Balb/c mice >C3H mice 
>C57B1 mice >rats.  In general, females were less responsive than 
males, with the exception of female C3H mice, which were more 
susceptible than the females of the other strains tested.  An 
association between the occurrence of acute toxicity and the 
reported carcinogenicity in the Swiss mouse was noted (section 
8.7.4).  Another comparison study also indicated marked strain and 
sex differences in the response of mice to vinylidene chloride 
[153].  The mice (10 males and 10 females per dose level) were 
exposed to 220, 400, or 800 mg vinylidene chloride/m3 (55, 100, or 
200 ppm) for 6 h/day, 5 days/week, for a total of 10 exposures.  
Only at 800 mg/m3 (200 ppm) were exposure-related deaths observed 
and the rates of mortality were greater in the males than in the 
females in Ha (ICR), CD-1 and CF-W mice, but no sex-related 
differences in mortality were observed in B6C3F mice.  Gross and 
histopathological examinations indicated that nephrotoxicity 
accounted for mortality in the male mice, but this was not the case 
in female mice.  Hepatotoxicity was considered to be the cause of 
death in Ha (ICR) and B6C3F1 mice.  The greatest sensitivity to 
renal toxicity was seen in male CF-W mice (a strain derived from 
the Swiss-Webster strain, believed to be genetically comparable to 
Maltoni's Swiss mouse).  

    The greater susceptibility to vinylidene chloride of mice 
compared with rats was also shown by Short et al.  [204], agreeing 
with the findings from acute single exposures (section 8.1).  After 
2 days exposure to 240 mg/m3 (60 ppm), 8/10 and 0/10 deaths were 
recorded in male CD-1 mice and male CD rats, respectively.  No 
mice survived a longer period of exposure at 240 mg/m3 (60 ppm).  
Serum glutamic oxaloacetic transaminase and glutamic pyruvic 
transaminase levels were raised in both rats and mice, but more so 
in the latter.  Severe hepatotoxicity and nephrotoxicity were 
observed in mice at autopsy.  

    A comparative study on the short-term toxicity of vinylidene 
chloride in male Sprague-Dawley rats and in both sexes of Swiss- 
Webster mice was reported by Oesch et al.  [156].  Animals (minimum 
of 10 per group) were exposed to an atmosphere containing 
vinylidene chloride at 40 or 200 mg/m3 (10 or 50 ppm) (mice) or 
800 mg/m3 (200 ppm) (rats) for 6 h, on 1, 3, or 8 days, and killed 
one day after the last treatment.  The majority of male mice 
exposed to 200 mg/m3 (50 ppm) for 8 days did not survive.  However, 
female mice survived this treatment as did rats exposed to 800 
mg/m3 (200 ppm).  Various changes in the activities of 
monooxygenase, epoxide hydrolase, and glutathione transferase 
enzymes occurred in animals treated with vinylidene chloride.  The 
enzyme changes could contribute to the relative susceptibility of 
the animals, according to the balance of activating and detoxifying 
activity.  In particular, cytosolic glutathione transferase 

activity towards the substrate 2,4-dinitrochlorobenzene was 
decreased in the kidneys of male mice (an organ susceptible to 
carcinogenicity (section 8.7.1)), but not in the kidney of rats or 
female mice or in the liver of either of these species (where 
activity was either unchanged or enhanced).  

    A study on rabbits has also been reported by Lazarev [116].  
Bronchitis, degenerative changes in the liver and kidney, and an 
increase in the rate of proliferation of lymphoid tissue in the 
spleen were observed in animals exposed to concentrations of 500-
2000 mg vinylidene chloride/m3 (125-500 ppm) for 3 h/day over a 
period of 4 months.  

    In summary, a number of studies have indicated the particular 
susceptibility of the male Swiss mouse to kidney toxicity.  This 
strain, sex, and species selectivity has important implications 
regarding the specificity of the carcinogenic action of vinylidene 
chloride (section 8.7.4).  

8.2.2.  Oral

    In a 90-day study, vinylidene chloride was incorporated in 
the drinking-water of male and female Sprague-Dawley rats at 
nominal concentrations of 0, 60, 100 or 200 mg/litre [152,176].  
Even at the highest concentrations administered (equivalent to 19-
26 mg/kg body weight daily), only minimal, reversible liver 
cytoplasmic vacuolation was observed, with no abnormalities in 
any of the other parameters investigated (section 8.2.1).  Maltoni 
& Patella [138] also noted a lack of lethality and clinical signs 
of toxicity in Sprague-Dawley rats (50 of each sex) orally dosed by 
gavage with 0, 0.5, 5, 10, or 20 mg vinylidene chloride/kg for 28 
consecutive days.  Four female and 4 male beagle dogs were given 
6.25, 12.5, or 25 mg vinylidene chloride/kg in peanut oil 
incorporated in gelatin capsules, daily for 97 days [177].  No 
significant differences were seen between these animals and 
controls with respect to appearance and demeanor, mortality, body 
weight, food consumption, haematology, urinalysis, clinical 
chemistry, and organ weights.  There was also no depletion in 
hepatic non-protein sulfhydryl levels in the liver or kidneys.  

     Some evidence for hepatotoxicity was provided by Siegers et al.  
[208] using higher levels of orally administered vinylidene 
chloride.  Male Wistar rats were given 0.125 g vinylidene 
chloride/kg in olive oil, by gavage, twice weekly for 2 weeks, 
followed by a similar treatment at 0.2 g/kg for 2 weeks.  
Hepatotoxicity was evidenced by mild increases in serum 
sorbitol dehydrogenase and aminotransferases.  Ethanol co-treatment 
(5% in drinking-water) with the 0.2 g/kg dose of vinylidene 
chloride enhanced toxicity leading to 6 deaths out of 10 animals.  
Simultaneous application of dithiocarb or (+)-catechin with 
vinylidene chloride led to total protection against lethal effects.  
The effects of these agents have been discussed elsewhere (section  

8.3.  Long-Term Exposure

    A number of studies described in this section are also 
discussed in section 8.7 in relation to carcinogenicity.  

8.3.1.  Inhalation

    Sprague-Dawley rats, 84-86 of each sex, 6-7 weeks of age at the 
start of the study, were exposed to vinylidene chloride vapour at 
0, 40, or 160 mg/m3 (0, 10, or 40 ppm) for, 6 h/day, 5 days/week, 
for 5 weeks, after which the levels of vinylidene chloride were 
changed to 0, 100, and 300 mg/m3(0, 25, and 75 ppm) [178,179,180].  
After exposure for a total of 18 months, the rats were observed for 
a further 6 months.  Additional animals were used for interim kills 
at 1, 6, and 12 months.  No clinical signs of toxicity were seen in 
the exposed groups.  Mean body weight gain was reduced at both dose 
levels during the period of 8-13 months in males, but was not 
reduced in females.  Mortality in exposed groups was only slightly 
higher than that in the controls (not different at the 40-100 mg/m3 
(10-25 ppm) dose levels in males) and only in the latter part of 
the study.  Histopathological studies indicated increased 
cytoplasmic vacuolation in the livers of exposed animals at 6 and 
12 months of exposure.  During the 6-month postexposure period of 
the study, the hepatic changes were no longer discernible, 
indicating reversibility.  

    There was also evidence of liver damage in CD-1 mice and CD 
rats (groups of 36 males and 36 females) exposed to 220 mg 
vinylidene chloride/m3 (55 ppm) (6 h/day, 5 days/week); the 
animals were about 2 months old at the start of the study.  Four 
animals of each species and sex were killed for examination after 
1, 2, 3, 6, and 9 months of treatment.  The remaining animals were 
killed at 12 months [118].  Groups of 100 animals were used as 
controls.  No effects were seen regarding haematology, clinical 
blood chemistry, pulmonary macrophage count, cytogenic analysis of 
bone marrow, X-ray examination of extremities, serum alpha-
fetoprotein, collagen content of liver, and lung and serum or 
urinary aminolevulinic acid (ALA) (collagen and ALA were not 
measured in the mice).  However, mice exposed to vinylidene 
chloride for 6-12 months had enlarged and basophilic hepatocytes 
with enlarged nuclei, focal degeneration, and necrosis.  A mild to 
markedly severe focal disseminated vacuolization of the liver was 
seen in the treated rats.  

    A similar long-term toxicity study was carried out by Hong et 
al.  [79] on male and female CD-1 mice and CD rats exposed to 220 mg 
vinylidene chloride /m3 (55 ppm) or filtered air (controls), for 6 
h/day, 5 days/week.  The numbers of rats used per sex group were 4, 
8, 8, and 14-16, and these were exposed for 1, 3, 6, and 10 months, 
respectively.  Mice (8, 8, and 12 animals per sex group) were 
exposed for 1, 3, and 6 months, respectively.  Animals were aged 2 
months at the start of the study and were observed for 12 months 
after treatment.  No histopathological changes were observed as a 
result of these treatments with vinylidene chloride.  A total of 
11/24 mice exposed for 6 months died or were terminated in a 

moribund condition (compared with 11/56 controls).  Only 3 rats died 
following exposure for 6 months or less (20/30 rats died in the 
group exposed for 10 months compared with 13/32 controls).  

    Long-term inhalation toxicity was also studied in rats, mice, 
and hamsters by Maltoni et al.  [141].  Groups of male and female 
Sprague-Dawley rats (60 of each) were exposed to 40, 100, 200, 400, 
600, or 800 mg vinylidene chloride/m3 (10, 25, 50, 100, 150, or 200 
ppm), for 4 h/day, 4-5 days/week, for 52 weeks.  Unexposed control 
groups consisted of 100 rats of each sex.  The rats were 16 weeks 
old at the start of the study.  At spontaneous death, hepatocyte 
vacuolization, cloudy swelling, fatty degeneration, necrobiosis, 
and necrosis were more frequent (57.6%) in rats exposed to 800-600 
mg/m3 (200-150 ppm) than in control animals (20.5%).  The highest 
tolerable dose for long-term exposure in rats was 600 mg/m3 (150 
ppm).  In Swiss mice (aged either 9 or 16 weeks at the start of the 
study) exposed to 40 or 100 mg vinylidene chloride/m3 (10 or 25 
ppm) for the same exposure periods (minimum of 30 mice per sex per 
dose level), changes were seen in the liver and kidneys that were 
compatible with changes seen in long-term studies on control 
animals.  However, a higher incidence of regressive or phlogistic 
changes was seen in the kidneys with renal adenocarcinoma (section 
8.7.1) at 100 mg/m3 (25 ppm).  A high mortality was seen at 200 
mg/m3 (50 ppm).  Those that survived only 4 exposures had hepatic 
fibrosis, which was considered to be due to repair of necrosis.  
Chinese hamsters (30 male and 30 female) exposed to a 
concentration of 100 mg vinylidene chloride/m3 (25 ppm) for 
periods identical to those given above for rats and mice, showed no 
signs of altered histology compared with controls (18 male and 17 
female) at spontaneous death.  

    Thus, the most significant observation on toxicity from long-
term inhalation studies is that of dose-dependent kidney damage in 
male Swiss mice at dose levels that were not nephrotoxic in female 
mice or in other species tested.  The findings have important 
implications in the light of similar tissue, sex, and species 
specificities in carcinogenicity (section 8.7.1).  

8.3.2.  Oral

    The long-term oral toxicity of vinylidene chloride was 
investigated by Maltoni et al.  [141] in Sprague-Dawley rats at 0.5, 
5, 10, or 20 mg/kg (given once daily by stomach tube, 4-5 
days/week, for 52 weeks).  Animals were aged 9 or 10 weeks at the 
start of the study.  Fifty animals of each sex were used per dose 
group with 100 controls (except for the 0.5 mg/kg group where there 
were 160 controls).  No signs of toxicity were reported from a 
complete autopsy after 147 weeks (or 136 weeks, 0.5 mg/kg) except 
that "hepatocyte vacuolization, cloudy swelling, fatty degeneration, 
necrobiosis, and necrosis were found in some animals in treated as 
well as in control groups".  

    In a separate study, 48 Sprague-Dawley rats of each sex (aged 
6-7 weeks at the start of the study) were given vinylidene chloride 
in the drinking-water at the following dose levels for 2 years: 7, 

10, or 20 mg/kg body weight for males and 9, 14, or 30 mg/kg for 
females (nominally 50, 100, and 200 mg/litre drinking-water).  
Eighty rats per sex were dosed as control groups without vinylidene 
chloride treatment [177, 179, 180].  Various parameters were 
monitored, as indicated for the 90-day study (section 8.2.1).  
Slightly increased cytoplasmic vacuolation of hepatocytes and 
hepatocellular fatty change were the only evidence of toxicity and 
occurred at all dose levels in the females, but only at 20 mg/kg 
body weight (200 mg/litre drinking-water) in the males.  

    A US National Toxicology Programme study [154] indicated 
chronic renal inflammation in male and female F344/N rats (50 per 
group) given 5 mg vinylidene chloride/kg in corn oil, by gavage, 5 
times/week, for 104 weeks.  At 1 mg/kg, no renal toxicity was 
observed.  In all treated rats, the clinical signs and histopathology 
of other organs were the same as in control rats.  This group also 
studied long-term oral toxicity in male and female B6C3F1/N mice 
(50 per group) administered 2 or 10 mg/kg in corn oil.  At 10 
mg/kg, necrosis of the liver was evident in male but not in female 
mice, but the reverse was true at the 2 mg/kg dose level.  However, 
the sponsors found defects in the conduct of the study and it could 
not be satisfactorily evaluated.  
    Ponomarkov & Tomatis [172] gave rats an oral dose of vinylidene 
chloride (50 mg/kg) weekly for the life span of the animal 
following an initial  in utero exposure (section 8.7.2 for details).  
Rats that died up to 30 weeks after the start of oral dosing (7/89 
males and 7/90 females) showed congestion of the lungs and 
kidneys.  At up to 80-90 weeks, haemorrhages and multiple lobular 
necrosis of the liver were observed.  The numbers of animals that 
survived for 90 weeks were 71/89 (males) and 75/90 (females) 
compared with 49/50 and 47/53 male and female controls, 
respectively.  Some of the treated survivors of 90 weeks showed 
degenerative lesions of liver parenchymal cells.  

8.4.  Toxicity  in vitro 

    As revealed in  in vivo studies ([145] section, 
 in vitro studies with rat liver microsomes showed that calcium pump 
activity was inhibited in a dose-dependent manner by vinylidene 
chloride in the presence of NADPH.  Malonic dialdehyde production 
(a consequence of lipid peroxidation) was not associated with 
inhibition of the calcium pump [182].  

    These findings stimulated Long & Moore [126] to test whether 
vinylidene chloride treatment of hepatocytes could raise cytosolic 
Ca2+ concentrations.  Isolated hepatocytes from Sprague-Dawley rats 
were exposed to vinylidene chloride (4 mmol/litre).  Within 5 min, 
the concentration of Ca2+ (estimated from the activity of 
glycogen phosphorylase a) was raised to 0.3 µmol/litre compared 
with 0.04 µmol/litre in vehicle-treated controls.  In separate 
studies, the concentration of Ca2+ was measured in hepatocytes 
loaded with quin 2 (a sensitive fluorescent indicator of 
cytoplasmic concentrations of ionized calcium).  Within 20 seconds 
of addition of vinylidene chloride at 4 mmol/litre, Ca2+ levels 

were increased from 0.26 ± 0.05 µmol/litre to 0.59 ± 0.06 µmol/litre.  
Disruption of intracellular Ca2+ homeostasis may prove to be a 
mechanism that can contribute to vinylidene chloride 

8.5.  Mutagenicity and Other Genotoxicity Assays

8.5.1.  Interaction with DNA

    The fact that a number of metabolites of vinylidene chloride 
are reactive and covalently bind to cellular macromolecules and the 
nucleophile glutathione has already been discussed in section 
6.1.5.  The specific covalent interaction with DNA has been little 
studied.  As reported in section, DNA binding  in vivo in 
rats and mice exposed to [14C]-vinylidene chloride at 40 mg/m3 (10 
ppm) (rats) and 40 or 200 mg/m3 (10 or 50 ppm) (mice) for 6 h was 
minimal, though DNA adducts were evident from the covalently bound 
radiolabel [186].  Adduct formation was greater in mice than in 
rats and greater in the kidneys than in the liver.  Binding was 
dose dependent in the kidneys of mice (equivalent to 30 adducts/106 
nucleotides at 200 mg vinylidene chloride/m3 (50 ppm) and 11 
adducts/106 nucleotides at 40 mg/m3 (10 ppm).  Incorporation of 
radiolabel into DNA during synthesis or contamination of DNA 
with other radiolabelled macromolecules cannot be excluded.  

    It was not possible to trap any alkylating metabolites  in 
 vitro with 4-(4-nitrobenzyl)-pyridine, following incubation of 
vinylidene chloride with a mouse liver microsomal system [15].  

8.5.2.  Genotoxicity in bacteria

    The mutagenicity of vinylidene chloride in bacteria has been 
demonstrated by a number of research workers and has been related 
to the asymmetry of the putative epoxide metabolite [73].  The 
positive effect was not seen in every study (Table 9) and in some 
cases this may have been due to volatilization of the compound.  
Vinylidene chloride (of unspecified purity) in air at 0.2, 2, or 
20% for 4 h induced revertants (gene mutations) in the TA1530 and 
TA100 strains of  Salmonella typhimurium in the presence of NADPH-
supplemented 9000-g liver supernatant (S9) from phenobarbital 
pretreated male OF-1 mice.  Mutagenicity towards TA100 was also 
catalysed by mouse kidney and lung 9000-g supernatants [14].  These 
authors demonstrated that mutagenicity was not due to the 
stabilizer 4-methoxyphenol.  The role of cytochrome P-450 in 
metabolic activation was evident from the lack of mutagenicity in 
the absence of NADPH and from the observed greater mutagenicity of 
vinylidene chloride towards  S.  typhimurium TA100 when mice used 
for S9 donation were pretreated with phenobarbital.  The role of 
reactive electrophiles in mutagenicity was supported by the marked 
inhibition of mutagenicity by the nucleophiles  N- acetyl-cysteine 
and  N- acetyl-methionine.  Protection against bacterial 
mutagenesis was also afforded by pretreatment of rats (which 
provided the hepatic S9) with pregnenolone-16 alpha-carnonitrile, 
amino-cetonitrile, or disulfiram [15].  The mechanism(s) of these 
effects are not known but may be via increased detoxification of 

vinylidene chloride or its metabolites.  In this study, 3-
methylcholanthrene as well as phenobarbital pretreatment of rats 
provided S9 that had up to 2-fold greater capacity than untreated 
rat liver preparations to activate vinylidene chloride (99% pure) 
to bacterial mutagens.  Liver specimens showing no pathological 
lesions, obtained from 4 adult human patients for diagnostic 
purposes provided S9 fractions that activated vinylidene chloride 
to mutagens detected by  S.  typhimurium TA100 at approximately 
one-fifth the activity of untreated mouse liver S9.  

    Jones & Hathaway [101] found vinylidene chloride (unspecified 
purity) to be only very weakly mutagenic in  S.  typhimurium strain 
TA1535 in the presence of liver (1.6 x background) and kidney (2.3 
x background) S9 from untreated male Alderley Park Swiss-derived 
albino mice.  Exposure was via the atmosphere (5% vinylidene 
chloride for 72 h) inside gas-tight culture vessels.  Use of S9 
from mice pretreated with Aroclor 1254 enhanced mutagenicity in 
the test.  In contrast, liver S9 preparations from male Sprague-
Dawley rats were able to mediate mutagenicity only after Aroclor 
pretreatment and at a mutation frequency approximately 25% of that 
seen with the corresponding mouse S9.  These data are in agreement 
with the greater oxidative metabolism observed in the mouse 
compared with the rat (section 6.1.4).  In this study, liver S9 
from uninduced marmoset or from a single, apparently uninduced, 
human subject was not able to mediate the bacterial mutagenicity of 
vinylidene chloride, though a positive result was obtained using a 
liver S9 from a human subject who had received long-term 
phenobarbital medication.  Thus, human beings appear to be more 
similar to rats than to mice with respect to hepatic metabolic 
activation of vinylidene chloride.  

    Exposure of  S.  typhimurium strain TA100 to 2% vinylidene 
chloride (99% pure) in air in the presence of a hepatic S9 fraction 
from untreated or phenobarbital-pretreated male OF-1 mice caused a 
linear increase in the mutagenic response up to 4 h of exposure 
[137].  This was in agreement with the dependence of bacterial 
mutagenicity on duration of exposure shown by Waskell [239].  
Again, phenobarbital pretreatment enhanced the metabolic 

    Oesch et al.  [156] detected the mutagenicity of vinylidene 
chloride (99.996% pure) with  S.  typhimurium strains TA1535,
TA1537, TA92, TA100, TA98, and  Escherichia coli strain WP2  uvrA
following exposure to vinylidene chloride in the atmosphere for 4
h at 1500-90 000 mg/m3 (375-22 500 ppm) and with an NADPH-
fortified liver S9 fraction from untreated male Swiss-Webster mice
as an activation system.  Again, it was established that the
inhibitor, methoxyphenol, was not mutagenic.  A comparative study
was made of kidney and liver S9 fractions from different species
regarding their ability to activate vinylidene chloride to
mutagens detected by  S.  typhimurium strain TA100.  The order of
ability to mediate mutagenesis was as follows: male and female
Swiss-Webster and C57BL/6J Han mouse liver and Chinese hamster
(Fue:FUST) liver >Sprague-Dawley rat liver >human liver
>Chinese hamster kidney >male mouse kidney (both strains) >rat
kidney and female mouse kidney.  Metabolic activation was not

accomplished or was very weak in the last two tissue samples.  As
with the study by Bartsch et al.  [14], mutagenicity was inhibited
by a nucleophile (in this case glutathione) and it was also found
not to be affected by the addition of purified microsomal epoxide
hydrolase to the test.  Despite changes in drug-metabolizing
enzymes as a result of pretreatment of rats and mice with
vinylidene chloride (section 8.2.1), S9 fractions derived from
treated animals were not found to have a greater metabolic
activation capacity in the mutagenicity assay.  

    The mutagenicity of vinylidene chloride towards  S.  typhimurium 
TA100 was detected by Baden et al.  [10, 11, 12] not only following 
gaseous exposure for 8 h at a level of 3% but also after incubation 
in suspension at 3% for up to 2 h.  In agreement with the data 
given above, Aroclor pretreatment of rats enhanced the ability of 
liver S9 to mediate vinylidene chloride mutagenicity and human 
liver S9 was also capable of catalysing the formation of mutagens.  
The mutagenicity of vinylidene chloride (unspecified purity) in 
liquid suspension assays (2.5 mmol vinylidene chloride/litre; 2 h 
incubation) was also shown to be positive by Greim et al.  [64], as 
evidenced by reverse gene mutation at one locus in  E.  coli strain 
K12.  When monitored for reverse gene mutation at 2 other loci, or 
forward mutation at 1 locus, a negative result was obtained, but 
only one dose level was used in this study.  

    Results of spot tests with  S.  typhimurium strains TA1950, 
TA1951, TA1952, TA1535, TA1538, TA100, and TA98 were reported 
briefly by Cerna & Kypenova [26].  Vinylidene chloride 
(unspecified purity) was added to plates at 1, 10, and 100% in DMSO 
(0.05 ml).  At 100%, vinylidene chloride produced reversion of 
both base substitution and frame-shift mutations in the absence of 
a metabolic activation system.  When tested in a host-mediated 
assay (female ICR mice) at doses quoted as LD50 and 50% LD50, a 
significant increase in the revertants of  S.  typhimurium TA1950, 
TA1951, and TA1952 was reported that was inversely related to dose.  

    A further brief report was given by McCarroll et al.  [129] in 
which vinylidene chloride (1.6 and 3%, "metabolically activated 
doses") was shown to be markedly mutagenic to  S.  typhimurium TA1535 
and TA100 in a microfluctuation assay involving a 72-h exposure.  

    Chloroacetic acid, a metabolite of vinylidene chloride, was 
found not to be mutagenic to  S.  typhimurium strains TA100, TA1535, 
TA1537, TA1538, and TA98 using a plate incorporation protocol 
without the addition of an S9 system [128].  Chloroacetic acid 
did not cause mutagenicity in  S.  typhimurium strain TA1530 in 
the presence or absence of S9 from phenobarbital-pretreated mice 

8.5.3.  Genotoxicity in yeast

    Bronzetti et al.  [19] studied the mutagenicity of vinylidene 
chloride (99.57% pure) in yeast.  Vinylidene chloride (0-50 
mmol/litre for 2 h preincubation in suspension) did not induce 

reverse gene point mutation or produce mitotic gene conversion in a 
diploid strain (D7) of  Saccharomyces cerevisiae in the absence of a 
microsomal activation system.  However, in the presence of a post- 
mitochondrial supernatant from mice pretreated with Aroclor 1254, 
a dose-related induction of revertants and convertants was seen 
between 30 and 50 mmol vinylidene chloride/litre.  Genotoxicity was 
also examined in yeast exposed to vinylidene chloride in an 
intrasanguinous host-mediated assay.  The host species i.e., male 
Swiss albino CD mice, were given vinylidene chloride orally in an 
acute single dose study (400 mg/kg) or in a short-term study (100 
mg/kg, 5 days per week followed by 200 mg/kg on the day of the 
assay).  The yeast cells (4 x 108) were injected via the retro-
orbital sinus immediately before the administration of vinylidene 
chloride on the day of the assay and were recovered from various 
organs 4 h later.  A positive result for the induction of revertants 
and convertants was found for yeast cells recovered from the liver 
and kidneys, but the results were negative or only very weakly 
positive for both parameters in cells from the lung.  

8.5.4.  Genotoxicity in plants

    After exposure to 5152 mg vinylidene chloride/m3 (1288 ppm) 
for 6 h, inactivation of a dominant gene (forward mutation) in 
 Tradescantia (hybrid clone 4430) was not observed [228].  However, 
at 88 mg vinylidene chloride/m3 (22 ppm) for 24 h, a positive 
result was recorded.  Although this finding indicates the 
potential for mutagenicity in plants, the dose-response 
relationship needs to be clarified.  

8.5.5.  Genotoxicity in mammalian cells  in vitro 

    Costa & Ivanetich [33] investigated the effects of vinylidene 
chloride (unspecified purity) on DNA repair (unscheduled DNA 
synthesis) in isolated hepatocytes from male Long-Evans rats that 
had been pretreated with phenobarbital.  When administered to 
hepatocytes at a maximum subtoxic dose level (2.1 mmol/litre), 
vinylidene chloride stimulated unscheduled DNA synthesis as shown 
by enhanced incorporation of deoxy-[5-3H]-cytidine into DNA.  

    However, the mutagenicity of vinylidene chloride was found to 
be negative when tested at two loci (induction of resistance to 8-
azaguanine and ouabain) in V79 Chinese hamster cells in the 
presence of a post-mitochondrial supernatant from phenobarbital 
pretreated rats and mice [43].  In this test, the V79 cells were 
exposed to 2 and 10% vinylidene chloride (unspecified purity) in 
air for 5 h.  This treatment led to dose-dependent cytotoxicity in 
the presence of rat but not mouse liver post-mitochondrial 
fractions.  Using a similar protocol, Huberman et al.  [82] 
demonstrated that the vinylidene chloride metabolite, mono- 
chloroacetic acid, in accordance with negative mutagenicity in 
bacteria (section 8.5.2), did not show any activity in inducing 8-
azaguanine and ouabain resistant mutants in Chinese hamster V79 
cells, when tested up to a level of 2.5 mmol/litre.  

    In a survey of the cytogenetic effects of 60 chemicals on 
cultured mammalian cells, Sasaki et al.  [193] reported that 
vinylidene chloride (3 x 10-2 and 3 x 10-3 mol/litre) failed to 
produce chromosomal breaks in Chinese hamster (Don 6) cells.  A 
microsomal metabolic system was not included in the assay.  Other 
research workers have also carried out cytogenetic studies on 
mammalian cells  in vitro.  McCarroll et al.  [129] analysed Chinese 
hamster ovary cells (CHO) for sister chromatid exchange following 
exposure to vinylidene chloride (unspecified purity).  Consistent 
and dose-related increases resulted from a 24-h exposure to 
atmospheres containing 1.8, 3.6, 5.4, or 7% vinylidene chloride.  
Only at 7% was the effect significant and shorter exposure 
periods provided negative results.  In this brief report it was not 
stated whether a mammalian hepatic microsomal fraction was included 
in the study.  Sawada et al.  [196] also investigated the ability of 
vinylidene chloride (99% pure) to induce chromosomal aberrations 
and sister chromatid exchange in a Chinese hamster cell line (CHL).  
Cells were treated for 6 h with a range of dose levels between 0 
and 2 mg/ml, at which toxicity was observed.  In the presence of a 
liver S9 fraction from PCB (KC-400)-pretreated male F344 rats, 
vinylidene chloride gave a relatively weak, but significant, 
increase in the incidence of sister chromatid exchanges.  The 
result was negative in the absence of S9.  The findings were similar 
when chromosomal aberrations were used as an end point for genetic 
toxicity.  In the presence (but not in the absence) of S9, a dose-
dependent induction of chromosomal aberrations was seen (14% 
aberrant cells at 0.25 mg/ml and 54% at 1.5 mg/ml).  These effects 
were not elicited by  p- methoxyphenol (the inhibitor).  The role 
of cytochrome P-450 in the metabolic activation of vinylidene 
chloride was shown by the inhibition of the enhancement of 
aberrations with metyrapone and a protective effect was seen by 
the addition of glutathione.  Two metabolites of vinylidene 
chloride, chloroacetyl chloride and chloroacetic acid, were 
negative in these tests in support of the theory that vinylidene 
chloride oxide may be the active genotoxic metabolite.  

8.5.6.  Genotoxicity in mammalian cells  in vivo 

    Evidence for the detectable but minimal covalent binding of 
[14C]-vinylidene chloride  in vivo has already been discussed [186] 
(sections and 8.5.1).  As part of this study, the ability 
of vinylidene chloride to induce unscheduled DNA synthesis (DNA 
repair) was also investigated in mice.  The measurement of DNA 
repair by the uptake of [3H]-thymidine into DNA was hampered by 
incomplete inhibition of replicative DNA synthesis by hydroxyurea.  

    Though unscheduled DNA synthesis was minimal,  the slight 
increase was statistically significant in mouse kidney at the 200 
mg vinylidene chloride/m3 (50 ppm) exposure level.  

    Short et al.  [203] investigated the incidence of germinal 
mutations of the dominant lethal type in 11 male CD rats exposed 
through inhalation of 220 mg vinylidene chloride/m3 (55 ppm) for 6 
h/day and 5 days/week.  During week 11 of exposure, the treated 
animals were housed with 2 virgin females until mating had taken 

place.  Neither pre-implantation nor post-implantation losses 
were observed in the pregnancies that resulted from mating with 
vinylidene chloride-exposed males; thus, dominant lethal mutations 
were not produced.  Anderson et al.  [3] also did not find any 
evidence for a dominant lethal effect.  Male CD-1 mice were exposed 
by inhalation to 40, 120, or 200 mg vinylidene chloride/m3 (10, 30, 
and 50 ppm), for 6 h/day, over 5 days.  Fifteen or 16 days after 
caging the males with untreated females (over a 2-month period), 
the females were killed for examination of the uteri.  As a result 
of toxicity, only 6/20 and 18/20 male mice survived exposure to 
vinylidene chloride at 200 and 120 mg/m3 (50 and 30 ppm), 
respectively.  No effects were seen in the frequency of pregnancy 
or in the number of post-implantational early fetal deaths.  There 
was also no evidence of pre-implantational egg losses as indicated 
by the total implants/pregnant female.  

    A number of  in vivo cytogenetic studies reported on vinylidene 
chloride have been unable to show a significant positive response.  
In the inhalation study by Lee et al.  [118] (details given in 
sections 8.3.1 and 8.7.1), cytogenetic analysis of bone marrow 
revealed no change following exposure of CD-1 mice or CD rats to 
220 mg vinylidene chloride/m3 (55 ppm) , for 6 h/day, 5 
days/week, for up to 12 months.  Cerna & Kypenova [26] gave single 
and repeated (l dose per day for 5 days) ip doses of vinylidene 
chloride to female ICR mice.  Neither a single dose (quoted as 1/2 
LD50) nor repeated doses (quoted as 1/6 LD50) induced chromosomal 
aberrations.  In the long-term study by Quast et al.  [178] (section 
8.3.1 for details), cytogenetic evaluations on 4 rats/sex exposed 
to 0, 100, or 300 mg vinylidene chloride/m3 (0, 25, or 75 ppm) for 
6 months did not show any adverse effects.  A negative  in vivo 
cytogenetic effect was also borne out by the work of Sawada et al.  
[196].  In this study, 6 male ddY mice per group were given 
vinylidene chloride (99% pure) by gavage, either as a single dose 
(0200 mg/kg) or as 4 doses (1100 mg/kg each) given at 24-h 
intervals.  No increase in the frequency of micronucleated 
erythrocytes was observed in the bone marrow.  A micronucleus 
test in the liver and blood of fetuses in vinylidene chloride-
treated mice was also negative (section 8.6).  These authors 
suggest that, in contrast to the  in vitro studies where positive 
genotoxicity has been found, the life time of the reactive 
metabolites of vinylidene chloride may be too short for a 
sufficient amount to have reached the target cells analysed  in vivo.  

    However, this conclusion conflicts with the findings of Hofmann 
& Peh [77] who studied chromosome aberrations in 50 metaphase bone 
marrow cells of 4 male and 5 female Chinese hamsters after short-
term inhalation (6 h/day, 5 days/week for 6 weeks) of either 120 or 
400 mg vinylidene chloride/m3 (30 or 100 ppm).  In comparison with 
control groups (fresh air), there was no effect on mortality but 78 
times more aberrations were observed in the animals exposed to 120 
mg vinylidene chloride/m3 (30 ppm) and 910 times more aberrations 
were seen at the 400 mg/m3 (100 ppm) dose level.  Using the same 
technique for analysis of chromosomal aberrations, Zeller & Peh 
[247] studied the effects of a single oral dose (216 mg/kg) in 
Chinese hamsters.  Animals that were killed 6 h after dosing showed 

a higher number of aberrations (1.6%) than animals given the same 
doses and killed after 24 h (1.2%) and 48 h (1.4%).  The untreated 
control animals showed the lowest rate of aberrations (0.6%).  No 
statistical test was carried out.  

8.5.7.  Summary

    Data on mutagenicity and other short-term tests for 
carcinogenicity are summarized in Table 9.  Genotoxicity has been 
observed in prokaryotic (in the presence of mammalian enzymes) 
and eukaryotic cells  in vitro.  However, genotoxicity was not 
observed in the majority of tests carried out on mammals  in vivo .  
Reports of an effect in the latter are restricted to the observation 
of chromosomal aberrations in the bone marrow cells of Chinese 
hamsters and the finding of a slight increase in DNA repair in the 
mouse kidney.  

8.6.  Reproduction, Embryotoxicity, and Teratogenicity

    Details of studies on dominant lethality in rats and mice are 
given in section 8.5.6.  These results provide no evidence for an 
adverse effect on male reproduction.  The fertility of male and 
female Sprague-Dawley rats and neonatal toxicity were investigated 
in a 3-generation, 2-litter study [151] in which test animals were 
continuously given drinking-water containing 0, 50, 100, or 200 mg 
vinylidene chloride/litre (99.5% minimum purity).  Ten male and 20 
female F0 rats were treated and 15 male and 30 female rats were 
used in the control F0 groups.  These animals were mated after 100 
days exposure (to provide F1a litters) and again 10 days after 
weaning of the first litter (to provide F1blitters).  Parents for 
the F2 and F3 generations were selected randomly from the F1b and 
F2 litters, respectively.  They were mated at 110 days of age to 
produce the F2 and F3a litters, respectively.  The F2 rats were 
then remated 10 days after weaning of the F3a and F3b litters to 
produce the F3b and F3c litters, respectively.  No evidence was 
found for an effect of vinylidene chloride on fertility, though 
marked fluctuations in the fertility index in all groups 
including the controls made interpretation of the results 
difficult.  Neonatal survival was lower in the F2 and F3a litters of 
dams ingesting vinylidene chloride than in the respective control 
groups but not lower than that of the historical data for the 
laboratory.  Furthermore, reduced survival in some litters was 
followed by normal survival in subsequent litters from the same 
adults.  It was concluded that the decreased survival was due to 
chance.  Necropsies were carried out on rats found dead or moribund, 
all weanlings not selected for future matings, and F1 and F2 adults 
after the litters were weaned.  

Table 9.  Summary of genotoxicity data for vinylidene chloride
Test system/End point of    Metabolizing              Dose               Resulta       Reference 
analysis                    system                    range

 Salmonella typhimurium 
(reverse gene mutation)
Strains TA 100, TA 1530     +  phenobarbital-induced  0.2-20% in air     + ve          [14,15]
                            mouse kidney, liver, and  for 4h
                            lung S9 mix

Strain TA 100               + phenobarbital-induced   0.2-20% in air     - ve          [14,15]
                            mouse liver S9 (-NADPH)   for 4h

Strain TA 100               + human liver S9 mix      2% in air for 4h   + ve          [15]

Strain TA 1530              + phenobarbital or        2% or 20% in air   + ve          [15]
                            3-methyl cholanthrene-    for 4 h
                            induced rat liver S9

Strains TA 100, TA 1535     ± rat or hamster S9 mix   0-3333 µg/plate    - ve          [146]
TA 98, TA 1537 "blind       (Aroclor induced)
study", preincubation

Strain TA 100               ± Aroclor-induced         3% for 2 or 8 h    + ve          [10, 11, 
                            rat liver S9 mix                                           12]

Strains TA 1950, TA 1951,   None                      1, 10, and 100%    + ve at       [26]
TA 1952, TA 1535, TA 1538                             in DMSO            100% dose
TA 100, TA 98 (spot test)                             (0.05 ml/plate)

Strains TA 1535, TA 1537,   + mouse liver S9 mix      1500-90 000 mg/m3  + ve          [156]
TA 92, TA 100, TA 98                                  for 4 h

Strain TA 100               + liver and kidney S9 mix 360-50 000 mg/m3   + ve          [156]
                            from mouse, rat, Chinese  for 4 h            (except where
                            hamster.  Also human                          S9 obtained
                            liver S9 mix                                 from female
                                                                         mouse kidney
                                                                         and rat kidney)
Table 9 (contd).  
Test system/End point of    Metabolizing              Dose               Resulta       Reference
analysis                    system                    range
Strain TA 1535              + mouse liver and kidney  5% for 72 h        + ve          [103]
                            S9 mix                                       (induction of
                                                                         S9 increased

                            + uninduced rat liver     5% for 72 h        - ve          [103]
                            S9 mix or marmoset or
                            human S9 mix

                            + induced rat liver       5% for 72 h        + ve          [103]
                            S9 mix

                            + uninduced marmoset      5% for 72 h        - ve          [103]
                            liver S9 mix

                            + uninduced human liver   5% for 72 h        - ve          [103]
                            S9 mix

                            + phenobarbital-induced   5% for 72 h        + ve          [103]
                            human liver S9 mix
 Escherichia coli 
(Reverse gene mutation)

Strain WP2  uvr A            + mouse liver S9 mix      1500-90 000 mg/m3  + ve          [156]
                                                      for 4 h

Strain K12                                            2.5 mmol/litre     + ve          [64]
(Forward and reverse gene                                                (for 1 locus
liquid suspension                                                        only)


 Salmonella typhimurium 

Strains TA 1950, TA 1951                              at LD50 and half-  + ve          [26]
TA 1952 host mediated                                 LD50 dose
in ICR mice
Table 9 (contd).  
Test system/End point of    Metabolizing              Dose               Resulta       Reference
analysis                    system                    range


 Saccharomyces (yeast)       ± Aroclor-induced rat     0-50 mmol/litre    + ve          [19]
(reverse gene mutation      liver S9 mix              for 2 h            (- ve without
and gene conversion)                                  preincubation      S9)

Chinese hamster V79 cells   ± Aroclor-induced rat     2, 20% for 2 h     - ve          [43]
(forward gene mutation)     liver S9 mix 

Chinese hamster V79 cells                             3x10-2 or 3x10-3   - ve          [193]
(chromosomal breaks)                                  mmol/litre

Chinese hamster ovary cells                           1.8-7% atmosphere  + ve          [129]
(sister chromatid exchange)                           for 24 h

Chinese hamster ovary       ± Aroclor-induced rat     0-2 mg/ml          + ve          [196]
cells (sister chromatid     liver S9 mix                                 (weak 
exchange)								 response)

Primary hepatocytes from                              2.1 mmol/litre     + ve          [32]
phenobarital-treated rats                             (maximum subtoxic
(unscheduled DNA                                      dose)

 Tradescantia (flower)                                 88 and 5152 mg/m3  + ve          [228]
(forward gene mutation)                                                  (at lower
                                                                         dose only)

 Saccharomyces (host                                   400 mg/kg or       + ve for      [19]
mediated assay in Swiss                               5x100 mg/kg daily  yeast cells     
mice                                                  plus 200 mg/kg on  recovered 
                                                      last day           from liver and   
                                                                         kidneys, but not
                                                                         from lung

Table 9 (contd).  
Test system/End point of    Metabolizing              Dose               Resulta       Reference
analysis                    system                    range
CD-1 mice and Sprague-                                rats: 40 mg/m3     + ve (but     [186]
Dawley rats (DNA adduct                               mice: 40 0r 200    minimal binding
formation in liver and                                mg/m3 for 6 h      detected)
kidney)                                                                  mouse > rat
                                                                         kidney > liver

CD-1 mice (unscheduled                                200 mg/m3          + ve (but     [186]
DNA synthesis in liver                                for 6 h            minimal); effect
and kidney)                                                              observed in 
                                                                         kidneys only

CD-1 mice (bone marrow                                220 mg/m3          - ve          [118]
cytogenetics                                          for 6 h, 5 days/week 
                                                      for 12 months

CD rats (bone marrow                                  220 mg/m3          - ve          [118]
cytogenetics                                          for 6 h, 5 days/week
                                                      for 12 months

Rats (male and female)                                0, 100, or 300     - ve          [178]
(bone marrow cytogenetics)                            mg/m3 for 6 months

ICR mice (bone marrow                                 One-half LD50      - ve          [26]
cytogenetics                                          one-sixth LD50
                                                      x 5 days

Male ddY mice (bone                                   0-200 mg/kg or     - ve          [196]
marrow micronucleus                                   0-100 mg/kg x 4
assay)                                                by gavage

Chinese hamster                                       120 or 400 mg/m3   + ve          [77]
(bone marrow                                          (30 or 100 ppm)
cytogenetics)                                         6 h/day, 5 days/week
                                                      for 6 weeks
Table 9 (contd).  
Test system/End point of    Metabolizing              Dose               Resulta       Reference
analysis                    system                    range

CD-1 mice (male)                                      40, 120, 200 mg/m3 - ve          [3]
(dominant lethal assay)                               6 h/day for 5 days

CD rats                                               220 mg/m3, 6 h/day - ve          [203]
(dominant lethal assay)                               5 days/week for
                                                      11 weeks
a  +ve = positive response.
   -ve = negative response.
    Absolute and relative kidney weights of weanling rats were 
comparable with controls.  No organ weight changes related to 
treatment were seen in F1 adults but elevated relative liver 
weights of female rats ingesting 200 mg vinylidene chloride/litre 
were seen in the F2 generation.  An increase in serum glutamic 
pyruvic transaminase (25% above control mean) was observed in 
female F2 rats at the 200 mg/litre level.  

    Signs of mild hepatotoxicity (fatty liver) were seen at 
treatment levels of 100 mg vinylidene chloride/litre and 200 
mg/litre in F1 and F2 rats and the incidence of chronic renal 
disease (though high in controls) was greater in male rats treated 
with 200 mg vinylidene chloride/litre than in control animals.  
Nitschke et al.  [151] concluded that vinylidene chloride treatment 
did not significantly affect the reproductive capacity of rats.  

    Sawada et al.  [196] investigated the incidence of micronuclei 
in fetal liver and fetal erythrocytes 24 h following exposure of 
pregnant ICR mice to 0, 25, 50, or 100 mg vinylidene chloride/kg 
(given by intraperitoneal injection).  No significant increase in 
micronuclei in these cells was observed as a result of treatment, 
and the results did not show any evidence of a transplacental 
passage of genotoxic metabolites or precursors.  

    In a study on Charles River CD rats (18-20 per dose group) and 
CD-1 mice (7-24 per dose group), Short et al.  [202] exposed animals 
to vinylidene chloride through inhalation at 60-1796 mg/m3 (15-449
ppm), for 22-23 h/day during various periods of organogenesis.  
On day 20 (rats) or day 17 (mice) of gestation, fetal abnormalities 
were seen at all dose levels in rats and a high incidence of early 
and complete resorptions was seen in mice exposed to vinylidene 
chloride concentrations >120 mg/m3 (30 ppm).  However, these 
effects were associated with a decreased weight gain and increased 
mortality in the dams.  Since similar fetal abnormalities of the 
soft tissues and skeleton occurred in a feed-restricted group of 
mice, the defects may be attributed to maternal toxicity.  In rats, 
malformations were seen in all groups and hydrocephalus was 
significantly increased in a dose-related manner from 2.5% in 
controls, 7.3% at 60 mg/m3 (15 ppm), 15.1% at 228 mg/m3 (57 ppm) to 
33.3% at 1200 mg/m3 (300 ppm).  Retarded ossification was seen in 
all treated groups.  Early resorptions were significantly increased 
from 2% in controls to 49% at 228 mg/m3 (57 ppm) and 64% at 1796 
mg/m3 (449 ppm).  Fetal weight was reduced in a dose-related 
manner and the reductions were significant at 228, 1200, and 1796 
mg/m3 (57, 300, and 449 ppm).  Food-restricted controls showed 
reduced fetal weight and retarded ossification but no significant 
increase in resorption rate or in the frequency of hydrocephalus.  
Aspects of maternal toxicity may be responsible for these effects.  
Part of this study involved an investigation of behavioural changes 
in Charles River CD rats (19 or 20 per dose group).  The rats were 
exposed to 224 or 1132 mg vinylidene chloride/m3 (56 or 283 ppm) 
for 22-23 h/day, on days 8-20 of gestation.  A dose-related weight 
loss over this period indicated maternal toxicity and the body 
weight of pups from the rats treated with 1132 mg/m3 (283 ppm) 
were lower than control weights (as with pups from feed-restricted 

rats).  Two groups of 3 pups/dose level and per sex were observed 
for activity in a maze for 2-4 months after birth.  Also one animal 
of each sex per dose level from each litter was subjected to pre-
weaning behavioural and physical maturation tests.  Maze activity 
was not affected by the vinylidene chloride treatment, nor were 
startle response, bar holding or swimming ability.  However, surface 
righting ability was delayed in pups from treated rats.  Tooth 
production was delayed in pups from the rats treated with 1132 
mg/m3 (283 ppm) (as in feed-restricted rats) but opening of the 
external ear was more rapid than in control pups.  In conclusion, 
the only adverse effects bserved could be attributed to maternal 
toxicity.  Murray et al.  [1979] investigated embryonic and fetal 
development in rats and rabbits following inhalation or oral 
ingestion (rats only) of vinylidene chloride (minimum purity 
99.5%) during gestation.  In the inhalation studies, Sprague-
Dawley rats (30-44 per dose group) and New Zealand White rabbits 
(18-20 per dose group) were exposed to 640, 320, or 80 (rats only) 
mg vinylidene chloride/m3 (160, 80, or 20 ppm), for 7 h/day, from 
days 6 to 15 (rats) and days 6 to18 (rabbits) of gestation.  Groups 
of 20-47 pregnant rats and 16 pregnant rabbits served as controls 
for each dose level.  For the ingestion study, 26 pregnant rats (24 
controls) received drinking-water containing vinylidene chloride at 
200 mg/litre (approximately 40 mg/kg per day) from days 6 to 15 of 
gestation.  Cesarean section was carried out on day 21 and day 29 
for rats and rabbits, respectively.  

    Although a teratogenic effect was not observed, some evidence 
of embryotoxicity and fetotoxicity was seen in rats and rabbits.  
In the rat inhalation study, there was delayed ossification and a 
dose-related increased incidence of wavy ribs at 320 and 640 mg/m3 
(80 and 160 ppm), concentrations that were toxic to the dams.  At 
80 mg/m3 (20 ppm), a concentration that was not maternally toxic, 
no embryo- or fetotoxic effects were seen.  In the rabbits, a dose 
of 640 mg/m3 (160 ppm) produced weight loss in the dams, increased 
resorptions, increased incidence of 13 pairs of ribs and delayed 
ossification of the fifth sternebra.  At 320 mg/m3 (80 ppm), there 
was no effect on dams or fetuses.  
8.7.  Carcinogenicity

    Details of a number of the studies described here have been 
provided in section 8.4.  In such cases, only an outline of the 
experimental protocol is given.  

8.7.1.  Inhalation

    In a long-term inhalation study (220 mg vinylidene chloride/m3 
(55 ppm)) carried out by Lee et al.  [118, 119] (section 8.3.1 
for details of treatments), haemangiosarcomas in the mesenteric 
lymph node or subcutaneous tissue were reported in 2 treated male 
rats and hepatic haemangiosarcomas were found in 2 male and 1 
female mice in the treatment group.  No haemangiosarcomas were seen 
in control animals.  Small bronchioalveolar adenomas were also 
reported in 6 male mice (17%) compared with 1 in the control group 
of male mice (4%).  The significance of this finding was considered 
questionable since, according to other reports, such adenomas, 

which occurred relatively late in the study, were common in 
untreated mice.  The numbers of animals used in the treatment and 
control groups in this study were very low (16 or less per group 
after 9 months) and the study was limited to 12 months, which is 
inadequate.  Furthermore, the authors referred to the spontaneous 
occurrence of hepatomas in mice at a similar age in other reports.  
In a follow-up study, it was not possible to repeat the finding of 
an increase in tumour incidence [79].  Intermittent exposure was 
limited to up to 10 months (rats) and up to 6 months (mice) at a 
vinylidene chloride concentration of 220 mg/m3 (55 ppm) (details 
given in section 8.3.1), and was followed by a 12-month observation 
period.  In contrast to the results of Lee et al.  [119], no tumours 
arose in the treated animals other than spontaneous tumours 
expected on the basis of their incidence in control animals.  In 
this study also, a small number of animals were used (14-16 rats 
and 12 mice per sex for 10- and 6-month treatments, respectively) 
and exposures were limited to periods of less than 12 months for 
both species.  

    The results of a number of other long-term inhalation studies 
on rats suggest a lack of carcinogenicity of vinylidene chloride in 
this species, but, as explained, these reports are not conclusive.  
Viola & Caputo [229] investigated the incidence of tumours in 51 
male and 23 female Wistar rats exposed to 800 mg vinylidene 
chloride/m3 (200 ppm) for 4 h/day, 5 days/week, for 5 months.  For 
the following 7 months, the concentration was reduced to 400 mg/m3 
(100 ppm) because of toxicity.  The animals were then given a 
complete autopsy at spontaneous death or after being killed when 
moribund.  Sprague-Dawley rats were also examined after exposure to 
400 mg/m3 (100 ppm) (30 of each sex) and 300 mg/m3 (75 ppm) (16 
and 21 male and female rats, respectively).  Thirty control rats of 
each sex were used for each strain.  No grossly observable 
correlation between tumour formation and vinylidene chloride 
inhalation was seen but a final report following the completion of 
microscopic examination of tissues and organs has not been 
released.  A more substantial study has been reported in several 
stages [134, 178, 179, 180].  The details of the long-term 
inhalation study on rats are given in section 8.3.1.  In outline, 
following the first month of treatment, animals of a relatively 
large group (minimum of 84 rats/sex per dose group) were treated 
intermittently with levels of up to 300 mg vinylidene chloride/m3 
(75 ppm) for the substantial period of 18 months and were 
sacrificed at 24 months.  The total incidence of tumours was 
similar in control and dosed animals, though the incidences of 
several tumours and/or tumour types were found to be statistically 
increased compared with the controls (P < 0.05, Fisher's Exact 
Probability Test).  These were not attributed to vinylidene 
chloride exposure on the basis of comparable historical control 
    The carcinogenicity of vinylidene chloride by inhalation 
was studied by Maltoni et al.  [139, 141] in rats, mice, and 
hamsters.  The experimental details for the long-term study are 
given in section 8.3.1.  The intermittent exposure levels were up 
to 100 mg/m3 (up to 25 ppm) (hamsters), 600 reduced from 800 mg/m3, 

(150 reduced from 200 ppm) (rats), and 100 mg/m3 (25 ppm) (mice) 
and were given over a period of 52 weeks.  The dose levels in rats 
and mice were limited by toxicity (section 8.3.1).  Animals were 
then observed until spontaneous death.  Tumour incidence in hamsters 
was not increased by treatment with vinylidene chloride.  The only 
type of tumour in treated rats for which the incidence was greater 
than that in the controls was in the mammary gland, but a dose-
response relationship was not observed and the authors suspected 
non-specific factors (linked to inhalation) to be responsible.  
As part of the same project, Maltoni et al.  [140] specifically 
investigated the ability of vinylidene chloride to produce brain 
tumours in Sprague-Dawley rats.  Groups of 30 rats of each sex were 
exposed to 40, 100, 200, or 400 mg vinylidene chloride/m3 (10, 25, 
50, or 100 ppm), and 60 rats per sex to 600 mg/m3 (150 ppm), for 4 
h/day, 4-5 days weekly, for 52 weeks (100 control rats were used 
per sex).  No evidence for the induction of brain tumours 
(ependymomas, gliomas, or meningiomas) was found.  

    A number of tumour-types were observed in mice [139, 141] 
including kidney adenocarcinomas, mammary tumours, pulmonary 
adenomas, and leukaemias.  The incidence of both mammary and 
pulmonary tumours (mainly adenomas) was statistically higher in 
treated mice compared with the controls (tested by the rank test of 
Krauth, Fisher's Exact Probability Test, Logrank test and probit 
analysis [142].  As with rats, non-specific factors may have been 
responsible.  However, a dose-response relationship was not 
observed in either case.  Kidney adenocarcinoma (a rare tumour in 
mice) was observed in 29 (28 male) out of 257 mice (300 at start) 
treated with 100 mg vinylidene chloride/m3 (25 ppm) and in 2 out of 
the 18 male surviving mice treated with 200 mg/m3 (50 ppm).  
Kidney adenocarcinomas were not seen in the 14 surviving females at 
200 mg/m3 (50 ppm), in mice treated with 40 mg/m3 (10 ppm) (0/60), 
or in control mice (0/380).  
    Maltoni et al.  [142] exposed two groups of approximately 
60 male and 60 female Sprague-Dawley rats to vinylidene chloride 
transplacentally, continuing the exposure by inhalation at birth 
(see Table 10).  Treatment of dams with vinylidene chloride at 400 
mg/m3 (100 ppm) through inhalation for 4 h/day, 5 days/week, 
was started when embryos were 12 days of age.  The inhalation 
treatment of dams and offspring was continued after birth with 
exposure to 400 mg vinylidene chloride/m3 (100 ppm) for 7 h/day, 5 
days/week over 8 or 97 weeks, giving a total exposure period of 15 
or 104 weeks.  Offspring may also have been exposed via ingestion of 
milk at the suckling stage.  

    An increased incidence of malignant neoplasias of the 
haemolymphoreticular system, generally classified as leukaemia, was 
observed in both males and females of both groups exposed to 
vinylidene chloride.  A slight decrease in body weight was also 
reported in these animals.  Although a quadrupling of leukaemia 
incidence appeared to occur in female rats and a doubling of these 
tumours occurred in the male rats, very little other information 
was reported.  It is possible that a few of the tumours called 
leukaemia are histiocytic sarcomas and should be classified 

separately from leukaemias.  Unless this is known, the 
contribution of this finding to the overall data base is 
compromised.  The authors pointed out that a considerable increase 
in total malignant tumours occurred in the rats exposed to 
vinylidene chloride for 104 weeks, when the treatment was started 
prenatally.  In contrast, a 52-week exposure of rats beginning in 
young adulthood (see above), showed no increased incidence of 
leukaemia at exposures as high as 600 mg/m3 (150 ppm) for 52 weeks, 
and only a borderline increase in total malignant tumours.  Both age 
at the start of exposure and the length of exposure appear to be 
important factors influencing tumour development in Sprague-Dawley 
rats exposed to vinylidene chloride.  

    Laib et al.  [114] investigated the occurrence of putative pre-
neoplastic nodules in the liver of rats treated with vinylidene 
chloride.  Neonate Wistar rats were exposed, together with 
mothers, to vinylidene chloride in the air at 440 ± 60 mg/m3 (110 
± 15 ppm) (8 h per day, 5 days per week).  Exposure to this 
concentration, did not result in increased lethality or reduction 
in body and liver weights.  Histochemical analysis of frozen liver 
sections, produced immediately after 6 weeks exposure, revealed 
ATPase-free islets, postulated to indicate preneoplasia.  
8.7.2.  Oral

    There have been three studies on the oral carcinogenicity 
of vinylidene chloride in which a reasonable number of rats were 
given a range of dose levels for an adequate length of time.  In the 
first [177, 179], vinylidene chloride was included in the 
drinking-water at a level up to 200 mg/litre (200 ppm) over a 2-
year period (details given in section 8.3.2).  No exposure-related 
neoplasms were detected.  Although the incidence of mammary gland 
fibroadenomas/ adenofibromas was greater in rats exposed to 50 
mg/litre than in the control animals, this increase was not dose 
dependent and was within the range of the historical control data 
for untreated rats.  

    In the second study [139, 141], vinylidene chloride was given 
by gavage in olive oil (details of animals and dosing regimen are 
given in section 8.3.2).  The intermittent dosing was over a 
period of 52 weeks and the animals were examined at spontaneous 
death.  No increase in tumours was observed in treated rats and, 
in particular, there was no increased incidence of mammary tumours 
(these being considered due to non-specific factors when found in 
the corresponding inhalation study (section 8.7.1)).  
    In a third gavage study [154], doses of 1 and 5 mg/kg were 
given daily to rats for 2 years (details in section 8.3.2).  No 
vinylidene chloride-related tumours were reported.  In mice 
(section 8.3.2), given 2 or 10 mg/kg daily for 2 years, though the 
incidence of lymphomas was increased at the lower dose level (P 
>0.05), this was not found at 10 mg/ kg and thus does not appear 
to be related to vinylidene chloride exposure.  However, the 
sponsors have recently found defects in the conduct of the study 
and it could not be satisfactorily evaluated.  

    A further study [172] was restricted to a single oral dose 
level given to BDIV rats throughout the life span from the time of 
weaning.  The study also included oral dosing of the mothers during 
pregnancy.  Twenty-four female pregnant rats were given vinylidene 
chloride orally (150 mg/kg) on the 17th day of gestation and 
their offspring (81 males and 64 females) were then treated weekly 
with 50 mg/kg (orally in olive oil) from the time of weaning.  All 
survivors were killed at 120 weeks or when moribund and all major 
organs, as well as those that showed gross abnormalities, were 
examined histologically.  Treatment did not increase the incidence 
of tumour-bearing animals, though liver tumours were increased in 
rats of both sexes (1/81 males and 3/80 females compared with 0/49 
and 0/47 in male and female controls, respectively), and 
meningiomas were increased in males (6/81 compared with 1/49 in 
controls).  The latter was found statistically to be not 
significant and, since a dose-response analysis was not possible, 
the results are inconclusive.  In addition, hyperplastic nodules 
were found in the livers of 2/23 females given the single dose of 
vinylidene chloride during pregnancy and also in 2/81 males and 
6/80 females among the progeny.  There was a significant difference 
( P =0.04) between treated and vehicle-treated control animals, no 
hyperplastic nodules being observed in the latter.  

8.7.3.  Other routes

    Van Duuren et al.  [227] studied the carcinogenicity of 
vinylidene chloride in groups of 30 female Ha: 1 CR Swiss mice 
following percutaneous and subcutaneous application compared with 
100 untreated control animals.  Following the application of 
vinylidene chloride at 121 mg/kg or 40 mg/kg in acetone to shaved 
dorsal skin, 3 times per week for between 440 and 594 days, 
animals were given a complete autopsy (except the cranial region) 
and abnormal-appearing tissues and organs were examined 
histologically.  Routine sections of skin, liver, stomach, and 
kidney were also taken.  Autopsies and additional sections from the 
injection site and liver were taken following the once weekly 
subcutaneous administration of 2 mg vinylidene chloride per mouse 
for the life span (78 weeks).  Although in the percutaneous study, 
benign lung papillomas (19/30, 12/30 and 30/100) were seen at 121 
mg/kg, 40 mg/kg, and 0 mg/kg, respectively, and stomach tumours 
were also observed at frequencies of 2/30, 0/30 and 5/100, 
respectively, the tumour incidence were not significantly elevated 
( P >0.05; Chi-square analysis) in any of the treatment groups.  
However, when vinylidene chloride was given as an initiating agent 
(single dermal dose of 121 mg/kg) followed 14 days later with 5 µg 
of the promoting agent phorbol myristate acetate three times 
weekly, for 428-576 days, 8/30 mice developed papillomas compared 
with 9/120 and 6/90 in control (phorbol myristate acetate-treated) 
mice and 1/30 treated mice developed a squamous cell carcinoma 
compared with 1/120 and 2/90 in control mice treated with phorbol 
ester (2.5 and 5.0 µg, respectively).  The incidence of papillomas 
in vinylidene chloride-treated mice was significantly greater 
than in the control groups ( P <0.005; Chi-square analysis).  The 
authors concluded that "initiating" activity was shown with 

vinylidene chloride but that it was not a complete carcinogen.  
However, the finding of papillomas in the phorbol myristate 
acetate-treated control mice and the low number of animals used in 
the treatment groups make the interpretation of the results 

8.7.4.  Summary of carcinogenicity

    A number of studies on rodents have been conducted that provide 
information on the potential carcinogenic action of vinylidene 
chloride (see Table 10).  In these studies, vinylidene chloride 
was administered by inhalation, orally by gavage and in drinking-
water, and by skin application and subcutaneous injection.  
Unfortunately, most of these studies were inadequate for the 
conclusive evaluation of carcinogenicity because of less than 
lifetime exposure regimens, insufficient numbers of animals, and an 
inadequate number of dose levels.  Only some of the studies were 
designed and conducted as cancer biossays.  

    Increased tumour incidence was not found, in most of the 
studies, but there were the following exceptions.  Kidney 
adenocarcinomas occurred in male Swiss mice exposed via inhalation 
to 100 or 200 mg vinylidene chloride/m3 (25 or 50 ppm) but not to 
40 mg/m3 (10 ppm).  This carcinogenic response may be related to 
the ability of vinylidene chloride to cause cytotoxic effects in 
the target organ (section 8.1.2 and 8.2.1).  In addition to kidney 
adenocarcinomas, statistically significant excesses of mammary 
carcinomas were observed in female mice and pulmonary adenomas in 
mice of both sexes, but in these cases there was no dose-response 
relationship.  In a 2-stage skin carcinogenicity assay in mice, 
there was some evidence that vinylidene chloride may have acted as 
an initiating agent.  

    In rats, an increase in mammary tumours that was not dose 
related was observed when adult animals were exposed through 
inhalation.  In separate study groups, a slight increase in 
leukaemias was observed in rats exposed through inhalation  in utero 
and then post-natally.  

Table 10.  Animal carcinogenicity studiesa
Species/      Route        Number of      Dose                 Duration of  Post-exposure  Result
strain        (Vehicle)    animals in                          administ-    period         ------------
[Reference]                each group                          ration                      male  female
                           male  female
Rat,          inhalation   100   100      0 mg/m3 (0 ppm)      4 h/day,     to             -      -
Sprague-                   30    30       40 mg/m3 (10 ppm)    4-5 days/    spontaneous    -      -
Dawley                     30    30       100 mg/m3 (25 ppm)   week,        death          -      -
[139,141]                  30    30       200 mg/m3 (50 ppm)   52 weeks                    -      -
                           60    60       600 mg/m3 (150 ppm)                              -      -

Rat,          inhalation   158   149      0 mg/m3 (0 ppm)      4/h day,     6 months       12/156 1/148
Sprague-      ( in utero   -     60c      0 mg/m3 (0 ppm)      5 days per                            
Drawley       and post     -     54b      400 mg/m3 (100 ppm)  week, 7 weeks,
[142]         natal        62    61       400 mg/m3 (100 ppm)  then 7 h/day,               10/61  4/61
              exposure)                                        5 days per                           
                                                               week, 97 weeks

                           60    60       400 mg/m3 (100 ppm)  4 h/day, 5   6 months       8/59   2/60
                                                               days per week,                       
                                                               7 weeks, then
                                                               7 h/day, 5 
                                                               days per week,
                                                               8 weeks

Rat, CD       inhalation   36    36       0 mg/m3 (0 ppm)      6 h/day, 5   none           -      -
[118, 119]                 36    36       220 mg/m3 (55 ppm)   days per     none           -      -

Rat, CD                                                        6 h/day, 5     52 weeks
[79]                                                           days per
                                                               week for:
              inhalation   4     4        0 mg/m3 (0 ppm)      1 month
                           8     8        0 mg/m3 (0 ppm)      3 months
                           8     8        0 mg/m3 (0 ppm)      6 months
                           16    16       0 mg/m3 (0 ppm)      10 months
                           4     4        220 mg/m3 (55 ppm)   1 month                     -      -
                           8     8        220 mg/m3 (55 ppm)   3 months                    -      -
                           8     8        220 mg/m3 (55 ppm)   6 months                    -      -
                           16    16       220 mg/m3 (55 ppm)   10 months                   -      -
Table 10.  (contd.)
Species/      Route        Number of      Dose                 Duration of  Post-exposure  Result
strain        (Vehicle)    animals in                          administ-    period         ------------
[Reference]                each group                          ration                      male  female
                           male  female

Rat,          inhalation   86    86       0 mg/m3 (0 ppm)
[179, 180]
[134, 178]                 86    86       40 mg/m3 (10 ppm)    6 h/day, 5   6 months       -      -
                                          first 5 weeks, then  days per week,
                                          100 mg/m3 (25 ppm)   18 months

                           86    86       160 mg/m3 (40 ppm)                               -      -
                                          first 5 weeks, then
                                          300 mg/m3 (75 ppm)

Rat, Wistar   inhalation   30    30       0 mg/m3 (0 ppm)      4 h/day, 5   to
[229]                                                          days per     spontaneous
                                                               week, for    death or
                           51    23       800 mg/m3 (200 ppm)  12 months    moribund state -      -
                                          first 5 months,      -
                                          400 mg/m3 (100 ppm)

Rat,          inhalation   30    30       0 mg/m3 (0 ppm)      4 h/day, 5   to             only gross
Sprague-                   16    16       300 mg/m3 (75 ppm)   days per     spontaneous    pathology
Dawley                     30    30       400 mg/m3 (100 ppm)  week, 12     death or       performed
[229]                                                          months       moribund
                                                                            state (22-
                                                                            24 months)

                                                                                            Kidney adeno-
Mouse, Swiss  inhalation   190   190      0 mg/m3 (0 ppm)      4 h/day, 5   up to 121      0/120  0/155
[139, 141]                 30    30       40 mg/m3 (10 ppm)    days per     weeks          0/24   0/26
                           150   150      100 mg/m3 (25 ppm)   week, 52                    28/119 1/138
Table 10.  (contd.)
Species/      Route        Number of      Dose                 Duration of  Post-exposure  Result
strain        (Vehicle)    animals in                          administ-    period         ------------
[Reference]                each group                          ration                      male  female
                           male  female
Mouse, Swiss               30    30       200 mg/m3 (50 ppm)   4 h/day, 4   to             2/18   0/14
(contd.)                                                       daysd         spontaneous
[139, 141]                                                                  death

                                                                                            Mammary gland
                                          0 mg/m3 (0 ppm)                                  1/180  3/187
                                          40 mg/m3 (10 ppm)                                0/30   6/30
                                          100 mg/m3 (25 ppm)                               1/148  16/148
                                          200 mg/m3 (50 ppm)                               0/52   6/54

                                                                                            Lung (mainly
                                          0 mg/m3 (0 ppm)                                  6/154  7/178
                                          40 mg/m3 (10 ppm)                                6/28   3/30
                                          100 mg/m3 (25 ppm)                               23/141 12/147
                                          200 mg/m3 (50 ppm)                               4/51   6/59

                                                                                           Tumours of the 
                                                                                           mammary gland 
                                                                                           and lung were
                                                                                           not dose-

Mouse, CD-1   inhalation   36    36       0 mg/m3 (0 ppm)      6 h/day, 5   none           -      -
[118, 119]                 36    36       220 mg/m3 (55 ppm)   days per     none
                                                               week, 52 

Table 10.  (contd.)
Species/      Route        Number of      Dose                 Duration of  Post-exposure  Result
strain        (Vehicle)    animals in                          administ-    period         ------------
[Reference]                each group                          ration                      male  female
                           male  female
Mouse, CD-1                                                                                Incidence of
(contd.)                                                                                   hepatic
[118, 119]                                                                                 haemangio-
                                                                                           sarcoma and
                                                                                           increased, but
                                                                                           this is not
                                                                                           thought to
                                                                                           have been
                                                                                           induced by
                                                                                           chloride [79]

Mouse, CD-1   inhalation                                       6 h/day, 5   52 weeks
[79]                                                           days per
                                                               week for:
                           16    16       0 mg/m3 (0 ppm)      1 month
                           16    16       0 mg/m3 (0 ppm)      3 months
                           28    28       0 mg/m3 (0 ppm)      6 months
                           8     8        220 mg/m3 (55 ppm)   1 month                     -      -
                           8     8        220 mg/m3 (55 ppm)   3 months                    -      -
                           12    12       220 mg/m3 (55 ppm)   6 months                    -      -

Chinese       inhalation   18    17       0 mg/m3 (0 ppm)      4 h/day,     to             -      -
Hamster                    30    30       100 mg/m3 (25 ppm)   4 - 5 days   spontaneous
[139, 141]                                                     per week,    death
                                                               for 52 weeks
Table 10.  (contd.)
Species/      Route        Number of      Dose                 Duration of  Post-exposure  Result
strain        (Vehicle)    animals in                          administ-    period         ------------
[Reference]                each group                          ration                      male  female
                           male  female

Rat,          oral         80    80       0 mg/litre (0 ppm)   daily for    none
Sprague-      (drinking-                                       24 months
Dawley        water)       
[179, 180]
[177]                      48    48       50 mg/litre (50 ppm)              none           -      -
                                          (M = 7 mg/kgbw)
                                          (F = 9 mg/kgbw)
                           48    48       100 mg/litre (100 ppm)            none           -      -
                                          (M = 10 mg/kgbw)
                                          (F = 14 mg/kgbw)
                           48    48       200 mg/litre (200 ppm)            none           -      -
                                          (M = 20 mg/kgbw)
                                          (F = 30 mg/kgbw)

Rat,          gavage       100   100      olive oil            daily        to
Sprague-      (olive oil)  82    77       (0 mg/kgbw)          4 - 5 days/  spontaneous
Dawley                     50    50       0.5 mg/kgbw          week, for    death          -      -
[139, 141]                 50    50       5 mg/kgbw            52 weeks                    -      -

                           50    50       10 mg/kgbw                                       -      -
                           50    50       20 mg/kgbw                                       -      -

Mouse, Swiss  dermal             100      0 mg                 3 x/week to  none                  -
Ha: ICR;      (in 0.2 ml         30       0.1 ml acetone       spontaneous  none                  -
[227]         acetone)           30       40 mg/mouse          death or     none                  -
                                 30       121 mg/mouse         moribund     none                  -
Table 10.  (contd.)
Species/      Route        Number of      Dose                 Duration of  Post-exposure  Result
strain        (Vehicle)    animals in                          administ-    period         ------------
[Reference]                each group                          ration                      male  female
                           male  female

Mouse, Swiss  subcutaneous       100      0 mg                 once per week
Ha: ICR;      (in 0.05 ml                                      649 days     none
[227]         trioctanoin)       30       0.05 ml water        636 days     none
                                 30       0.05 ml              631 days     none                  -
                                 30       2 mg/mouse           548 days     none                  -

Mouse, Swiss  dermal             30       121 mg/mouse         once, to     none           8/30 
HA: ICR;      (initiation                 then 5 mg PMAe       spontaneous                 papillomas
[227]         test on the                 per animal           death or                    1/30 skin
              skin)                                            moribund                    carcinoma
                                                               state; PMA
                                                               3 x/week
a  Modified from: ECETOC [45].
b  Only 2 treatments, because of the high toxicity.
c  Pregnant females.
d  Only 4 treatments, because of the high toxicity and mortality.
e  PMA = phorbol myristate acetate.

9.1.  Single and Short-term Exposures

    According to Gibbs & Wessling, [59], exposure to a high 
concentration of vinylidene chloride, e.g., 16 000 mg/m3 (4000 
ppm), rapidly causes intoxication that can lead to unconsciousness.  
The anaesthetic effects from short-term exposure are short-lived.  
At unspecified sub-anaesthetic doses, prolonged exposure and 
repeated short-term exposures may produce kidney and liver damage 

    Some adverse effects associated with vinylidene chloride 
exposure have been attributed to contaminants or to the stabilizer 
( p- methoxyphenol).  Henschler et al.  [74] reported the occurrence 
of persistent cranial nerve disorders in two individuals who had 
attempted to clean out tanks that had contained vinylidene chloride 
co-polymers.  The chemical responsible for this effect appeared, 
however, to be a contaminant of vinylidene chloride (either mono- 
or dichloroacetylene).  Chivers [29] reported the incidence of 
leukoderma in two subjects following skin contamination with 
 p- methoxyphenol.  The irritant effect of vinylidene chloride [84, 
192] on the eye, upper respiratory tract (at levels as low as 100 
mg/m3 i.e., 25 ppm) [192], and skin may be at least partially due 
to the stabilizer  p- methoxyphenol and, in the case of the study 
by Rylova [192], other impurities.  Dermatitis was reported in an 
individual whose skin was directly exposed to Saran film 
(vinylidene chloride/ vinyl chloride co-polymer in the absence of a 
stabilizer) [160].  
9.2.  Long-Term Exposure

  A quantitative risk estimate based on the best available set 
of data (mouse-kidney adenocarcinoma) from the animal tumour 
assays, using a non-threshold mathematical model, linear at low 
doses, provides an estimate of an upper limit of human risk [225].  
The true risk is not likely to be greater than this estimate and 
may be lower.  The upper limit for human risk thus estimated was 
5.0 x 10-5 for a continuous lifetime exposure to 1 µg/m3 in air and 
3.3 x 10-5 for ingestion of drinking-water containing 1 µg/litre.  
However, in the light of the discussion in section 8.6.4, the 
limited evidence for carcinogenicity in animal models is not 
sufficient to reach a firm conclusion on the carcinogenic risk of 
vinylidene chloride for human beings.  

    Interpretation of epidemiological studies on the effects of 
vinylidene chloride in human beings has been confounded by 
concomitant exposure to vinyl chloride.  A mortality study on 629 
workers exposed to vinylidene chloride, for 6-10 h/day, 42 h/per 
week, for various lengths of time in a vinylidene chloride 
production and polymerization plant in the Federal Republic of 
Germany was reported by Thiess et al.  [219].  Individuals were 
exposed to an estimated (unmeasured) average plant concentration 
of 200 mg vinylidene chloride/m3 (50 ppm) from 1955 to 1965 and 

subsequently to an average level of approximately 40 mg/m3 (10 
ppm) up to 1975, based on measurements of airborne contamination 
after 1975.  All had also been exposed to vinyl chloride (measured 
as <13 mg/m3 ( <5 ppm) since 1975) and acrylonitrile (measured as 
<2 mg/m3 (<1 ppm) since 1975).  A 97% tracing was obtained for 
follow-up analysis of the majority (447) of the cohort that was 
exposed for more than 6 months.  The incidence of exposure for >1 
year in the remainder, was 36% and tracing for follow-up analysis 
was only 24%.  The mortality rate of the cohort was compared with 
that of two populations of 180 000 (local) and 3 700 000 (regional) 
for the period 1969-75.  The expected number of deaths was 
calculated by applying age-specific mortality rates to the person-
years of observation of 7 age groups within the cohort.  
Statistical evaluation was based on the Poisson distribution.  The 
distribution of deaths according to age and decade (total 39 
deaths) indicated that workers in the exposure groups did not have 
an elevated mortality rate (total 57 and 36 expected from the data 
of the two reference populations).  The expected numbers of deaths 
resulting from cancers, infectious diseases, cardiovascular 
diseases, other natural causes, and external causes were compared 
with the observed incidence.  

    Although the number of deaths from cardiovascular diseases in 
general was not different from that expected, a peculiar 
distribution of deaths caused by cerebral haemorrhage in the young 
age groups deserves mention.  The occurrence of several deaths 
attributable to cerebral haemorrhage, cerebral sclerosis/apoplexia,
and acute coronary failure in age-groups below 50 years was beyond 
chance ( P- values far below 0.05).  But this study did not verify 
the validity of diagnoses on death certificates and adequately 
designed studies are needed to ascertain this part of the mortality 
    Five deaths (out of 39) through suicide compares with 2.5-3.0 
expected.  This cause of death does not rely on diagnostic validity 
and indicates the need for further investigations, because suicide 
may relate to mental depression.  Bronchial carcinomas were seen 
in 5 individuals compared with expected numbers of 3.9 and 2.2 
from the data on the two control populations.  It was noted that 3 
of the subjects with bronchial carcinoma were heavy smokers, the 
remaining 2 cases (observed at age 37) were clearly in excess of 
the expected incidence in the age-group below 40 (0.08 and 0.07 for 
the 2 reference populations,  P = 0.003).  The incidence of 
oesophageal cancer was within the range of age-specific expectation 
for the larger (district) control population but not for the 
smaller city population.  The authors concluded that the overall 
malignant tumour incidence was not statistically different from 
the expected rate.  
    More detailed information was provided in a follow-up 
investigation of this exposed population (535 persons exposed for 
more than 6 months) [110].  In this extended analysis with an 
estimated average exposure in the years before 1965 of 200 mg/m3 
(50 ppm), the observed total number of deaths (48) was 
significantly greater than that expected from the reference 

populations (43.2-46.5) due to a greater incidence of 
cardiovascular disease (20 observed deaths versus about 15 
expected).  Eleven deaths from myocardial infarction were 
statistically significantly in excess of the 6.8 expected.  The 
number of malignant tumours was 12 compared with 9.8 expected and 
this was reflected in the incidence of bronchial carcinomas (6 
compared with 2.68-2.96 expected).  In comparison with internal 
reference groups not exposed to vinylidene chloride, the cancer 
deaths were statistically in excess (3 of the lung-cancer cases 
were aged under 50).  However, this statistically increased 
incidence was not considered to be related to vinylidene chloride 
exposure since, in 2 cases, exposure was limited to 2 years 
duration.  The interpretation of the epidemiological study is 
hampered by a low cohort number, while co-exposure to other 
chemicals, such as vinyl chloride, was only considered in part by 
the inclusion of internal reference populations.  

    In a further epidemiological study [240], employees had been
exposed to different extents to a range of substances in synthetic
chemical plants.  These investigators combined detailed work
histories of 4806 individuals with exposure ratings for each of 19
chemicals during each calendar year from 1942 to 1973.  After
construction of a serially additive expected dose model, the
authors tested whether vinylidene chloride was responsible for the
observed excess risk of lung cancer in the cohort by using the
one-sided t-test of the observed minus expected cumulative doses
over all years and for ten or more years before death.  No
relationship was found between vinylidene chloride exposure and
lung cancers.  

    The only epidemiological study of individuals exposed to 
vinylidene chloride where vinyl chloride was not used as a 
co-polymer (ethyl acrylate was the co-polymer) was carried out by 
Ott et al.  [166].  Employees (138) were exposed to time-weighted 
average (TWA) concentrations ranging from 20 to 280 mg vinylidene 
chloride/m3 (5 to 70 ppm) for a minimum of one year, within the 
period 1942-65.  No association was found between exposure and 
mortality ascertained in 1974 among this low cohort number, when 
compared with US national statistics.  Two employees suffered 
hepatic damage, but, in both cases, alcohol consumption was known 
to prevail.  The size of the cohort having a long duration of 
exposure or a long latency period since initial exposure was small.  
No internal comparison was made, comparable to the approach by 
Klimish et al.  [110].  Although the results of the epidemiological 
studies do not provide convincing evidence for an increased risk 
of cancer in human beings exposed to vinylidene chloride, it is not 
possible to conclude that there is no carcinogenic effect.  It 
should be remembered that inadequate studies often tend to 
underestimate rather than to overestimate an association between 
exposure and cancer.  
    Schmitz et al.  [198] assessed serum glutamic oxaloacetic 
transaminase, glutamic pyruvic transaminase, and gamma-glutamyl 
transpeptidase in 133 human subjects exposed to vinylidene 
chloride, as a test for liver damage.  Serum enzyme levels changed 
less in two comparison groups than in the exposed group but, 
according to Fisher's Exact Probability Test, the duration of 
exposure to vinylidene chloride did not influence the serum enzyme 

10.1.  Evaluation of Effects on the Environment

    As a result of volatilization, the atmosphere is the major 
environmental compartment for vinylidene chloride.  The half-life of 
vinylidene chloride in the troposphere is expected to be 
approximately 2 days and therefore the compound is unlikely to 
participate in the depletion of the stratospheric ozone layer.  
Leaching and volatilization render soil and sediments minor 
compartments for vinylidene chloride in the environment and the 
level of this chlorinated hydrocarbon in the aqueous environment is 
also minimized by rapid volatilization.  It is not known whether 
the degradation of compounds, such as trichloroethylene and 
perchloroethylene, which are often found in water, contributes in a 
significant manner to the levels of vinylidene chloride found in 
the environment.  

    The concentrations of vinylidene chloride found in 
environmental waters and the acute toxicity levels for fish and 
 Daphnia indicate that acute toxic risks for the aquatic environment 
are minimal.  Available data on long-term toxicity are insufficient 
to assess sub-lethal effects on any aquatic organisms residing near 
point sources of relatively high levels of vinylidene chloride 
contamination, such as contaminated ground water and municipal and 
industrial outfalls.  
10.2.  Evaluation of Human Health Risks

10.2.1.  Levels of exposure

    The general population is exposed to very low levels of 
vinylidene chloride.  The maximum level reported in drinking-water 
is 20 µg/litre, though the average daily individual exposure of USA 
citizens via drinking-water has been estimated to be <0.01 µg.  
The levels of vinylidene chloride in food are generally not 
detectable and levels above 10 µg/kg have not been reported.  The 
levels in food derived from aquatic organisms are not known, but 
are likely to be insignificant (section 10.1).  Ambient air levels 
of vinylidene chloride have been reported of up to 52 µg/m3 (at the 
perimeter of an industrial site).  Median urban air concentrations 
in the USA of 20 ng/m3 and 8.7 µg/m3  have been reported for non-
industrial and industrial-source areas, respectively.  

    Occupational exposure occurs particularly in production and 
polymerization processes.  Respiration is the major route of uptake 
and the maximum recommended or regulated mean exposure limits over 
the period of a working day range from 8 to 500 mg/m3 (or the 
lowest reliably detectable concentration) depending on the 
country.  Short-term exposure limits range from 16 to 80 mg/m3 and 
ceiling values range from 50 to 700 mg/m3.  Airborne levels of 
vinylidene chloride in the confined atmospheres to which workers in 
certain occupations are exposed have been found not to exceed 8 

10.2.2.  Acute effects

    In human beings, inhalation of high concentrations of 
vinylidene chloride (very approximately, at or above the maximum 
olfactory threshold of 4000 mg/m3) are likely to cause depression 
of the central nervous system and could lead to coma.  On the basis 
of acute toxicity in animals, toxic effects of vinylidene chloride 
may occur in the liver, kidneys, or lungs at well below the 
minimum olfactory threshold of approximately 2000 mg/m3.  
Vinylidene chloride exposure can lead to irritation of the eye, the 
upper respiratory tract (at 100 mg/m3 in human beings (section 
9.1), and the skin, and this is thought to be partially due to the 
stabilizer  p- methoxyphenol.  

    In mice, which are more susceptible than rats to the 
hepatotoxic and renal toxic effects of vinylidene chloride, 
kidney damage was induced by exposure to as little as 40 mg 
vinylidene chloride/m3 (10 ppm) for 6 h.  Marked hepatotoxicity and 
renal toxicity were also seen in rats.  After fasting, which 
exacerbated toxicity, exposure to vinylidene chloride at 600 mg/m3 
(150 ppm) and 800 mg/m3 (200 ppm) for 6 h caused toxicity in rat 
liver and kidney, respectively.  Studies on rats indicate that 
alcohol ingestion prior to exposure can enhance the metabolism and 
exacerbate the toxicity of vinylidene chloride.  Acute toxicity is 
dependent on species, sex, strain, and the dietary status of 
animals.  Species susceptibility is correlated with the activity 
of oxidative metabolism of vinylidene chloride in rats and mice.  
While it is not possible to predict whether the rat or the mouse 
provides the more suitable model for human beings, the activity of 
hepatic microsomal metabolism by human beings is quantitatively 
similar to that of the rat, a species of relatively low 
susceptibility.  There is no evidence of a qualitative difference 
in the oxidative metabolism of vinylidene chloride in human beings 
and rodents.  

    It is apparent that the margin between the concentrations 
capable of producing toxicity in animals (40 mg/m3 in mice) and the 
occupational exposure limit set by some countries may not be 
sufficient or may be non-existent.  

10.2.3.  Long-term effects and genotoxicity

    Prolonged and repeated short-term exposures at sub-anaesthetic 
doses may produce kidney and liver damage.  On the basis of long-
term studies on animals, under conditions that simulated 
occupational exposure, hepatic changes were reported at an exposure 
level of 300 mg /m3 (75 ppm) in rats.  In mice, kidney and liver 
damage were seen at 100 mg/m3 (25 ppm) and 200 mg/m3 (50 ppm), 
respectively.  There was considerable variation in the sensitivity 
to toxic effects observed in the different studies.  

    Vinylidene chloride does not appear to affect reproductive 
capacity or to pose an embryotoxic or teratogenic risk at dose 
levels below those required for maternal toxicity in animals, but 

this has not been studied in human beings.  Embryo and fetal 
toxicity and fetal abnormalities were seen at levels producing 
maternal toxicity, as evidenced by reduced weight gain.  

    Vinylidene chloride is mutagenic for bacteria and yeast 
provided that a mammalian metabolic system is present.  Some 
mammalian cells are also receptive to DNA damage and mutagenicity 
 in vitro .  Genotoxicity was not evident in the majority of  in vivo 
studies on rodents, as measured by dominant lethality and 
cytogenetics, but aberrations in bone marrow cells of Chinese 
hamsters have been reported.  DNA binding and repair  in vivo in 
rodents, though detectable, was minimal.  The data on  in vivo 
genetic studies therefore suggest some evidence for genetic 
toxicity, but, in the majority of studies, the effects were 
minimal or negative.  

    Several carcinogencity tests have been carried out on three 
species of experimental animals (mouse, rat, and hamster) using 
various routes of administration.  Unfortunately, most of these 
studies suffered from severe limitations in design or conduct for 
carcinogenicity evaluation.  No significant carcinogenic effects 
were observed in rats dosed orally.  In adult rats exposed through 
inhalation, an increase in mammary tumours, which was not dose-
related, was reported.  A slight increase in leukaemia was observed, 
when rats were exposed both  in utero and post-natally.  These 
observations could not be evaluated.  In one study on mice, 
increased incidence of kidney adenocarcinomas were observed in 
males at exposure levels of 200 and 100 mg/m3 (50 and 25 ppm) but 
not at 40 and 0 mg/m3 (10 and 0 ppm).  In the same study, 
statistically increased incidences of lung tumours (mainly adenomas 
in both sexes) and mammary carcinomas (in females) were observed, 
but no dose-response relationships were found.  

    The kidney tumours may be related in some way to observed 
kidney cytotoxicity and it is possible that repeated kidney damage 
either leads directly to the carcinogenic response via a non-
genotoxic mechanism or facilitates the expression of the genotoxic 
potential of metabolites in this particular species, sex, and 
organ.  However, this conclusion is uncertain in the absence of 
adequate dose-response data on genetic effects  in vivo and the 
findings that vinylidene chloride may have acted as an initiator in 
a two-stage skin assay in mice.  

    Epidemiological studies, while not providing any statistically 
significant evidence for an increased cancer risk from vinylidene 
chloride exposure under occupational conditions, are not adequate 
to permit a proper evaluation of the carcinogenic risk of 
vinylidene chloride for human beings.  

    Although the evaluations of individual authors dismiss the 
finding of excess cancer deaths as a chance occurrence (due to 
small numbers and cohort sizes), the consistency of the higher than 
expected values is worth mentioning.  In the two cohort studies 
reported, lung cancer was observed in 7 cases, whereas 3.16 deaths 

would have been expected.  The result cannot be dismissed, but co-
existent exposure to vinyl chloride (in one study) has to be borne 
in mind.  Since the cohorts were identified according to their 
exposure to vinylidene chloride, it may be impossible to exclude 
additional confounding exposures.  

    The morbidity findings reported (including one case of 
testicular carcinoma) have some informatory value.  The 
interpretation by the authors that higher liver morbidity was 
related to the alcohol consumption of the individuals is invalid, 
since the alcohol intake by all members of the study (not only 
that of identified cases) was not assessed.   

11.1.  Recommendations for future work

    There is a need for better estimates of the global annual 
production of vinylidene chloride and of the amounts of vinylidene 
chloride entering the environment from all sources, whether arising 
from the release of vinylidene chloride as such or from the 
degradation of other chemical products.  
    The predicted environmental fate is based on little 
experimental evidence.  Information is required on rates of 
degradation and on transformation products in the air, soil, 
water, and sediment, and metabolism in representative non-
mammalian species.  

    Long-term toxicity studies investigating a variety of 
pathological endpoints should be carried out on representative 
aquatic species (fish, crustacea, and molluscs).  

    Thresholds for, and mechanisms of, toxic effects from short- 
and long-term exposure to vinylidene chloride need to be defined 
more accurately in animals and human beings, as a basis for 
establishing safe levels of exposure.  

    More exhaustive use should be made of existing data on 
carcinogenicity.  If further carcinogenicity studies are carried 
out, they should be conducted according to an accepted lifetime 
bioassay protocol specifically designed to cater for the particular 
properties of vinylidene chloride.  Such studies should take into 
consideration the short half-life of the chemical in the body, 
the importance of age at onset of exposure, the daily exposure 
duration, and other relevant information that might be related to 
determining the dosing regimen.  Species and strains of animals for 
testing need to be carefully selected.  Toxicity data as well as 
metabolic and pharmacokinetic data for these animals would also be 
extremely useful.  

    Epidemiological studies are needed to enable an assessment to 
be made of the effects of exposure to vinylidene chloride 
(including prolonged low-level exposure) on human populations.  
Thus, long-term follow-up studies on morbidity and mortality on 
whole, unselected populations exposed to vinylidene chloride 
should be conducted.  Information on effects, such as premature 
cerebrovascular disease and cancer, is particularly necessary and 
studies should take into account confounding factors, such as 
smoking and alcohol consumption (ideally on a case-referent basis).  

    To overcome the problem of small numbers in individual production 
sites, multicentre studies with pooling of data may provide a 
valuable approach in both ongoing and future investigations.  
Historical data should be used as a reference basis for comparison 
with results from ongoing investigations to enable an assessment to 
be made of the protective effects of regulatory action over recent 

    There is a need to compare the  in vivo/in vitro pharmacokinetics 
and metabolism of vinylidene chloride, especially in the kidney, 
liver, and lungs, in experimental animals of different species 
and in human beings, in order to better understand the results 
obtained in  in vivo toxicity studies.  Parallel data are required 
on the potential genotoxicity of vinylidene chloride at the target 
site for carcinogenesis in different species, to examine the 
possible role of a genetic mechanism.  

    In the light of the neurotoxicological findings reported in 
this review, there is a need to investigate the role of modulator 
systems in the pathogenesis of vinylidene chloride intoxication.  

    The value of the use of a sulfydryl agent, such as 
 N- acetylcysteine, in the treatment of vinylidene chloride 
poisoning in human beings should be investigated in experimental 
animal studies.  

11.2.  Personal Protection and Treatment of Poisoning

11.2.1.  Personal protection

    In industrial situations where short-term inhalation exposures 
above the recommended limits are possible, full face masks with 
filters for organic vapours should be used and, where necessary for 
emergency use, masks with air-line supply systems should be 
provided.  Properly maintained protective clothing including 
safety goggles should be worn by those handling vinylidene 
chloride, to prevent contact with the body.  A constant air flow 
should be maintained within industrial plants with adequate 
filtered vents at points where spills or leaks are likely to occur.  
The monitoring of vinylidene chloride emissions during distribution 
operations is recommended.  In the event of a leak, the vinylidene 
chloride should be evaporated either directly in the case of small 
leaks, or by controlled evaporation using an expansion synthetic 
foam.  Water spray curtains can be used to disperse the vapour from 
the foam.  

11.2.2.  Treatment of poisoning in human beings

    In cases of over-exposure or ingestion, medical advice should 
be obtained.  Because of the irritant properties of vinylidene 
chloride, particular attention should be given to the lungs, skin, 
and eyes.  The functions of the heart, liver, kidney, and central 
nervous system should be monitored.  Since the animal data have 
indicated that vinylidene chloride produces a marked increase in 
sensitivity to epinephrine-induced cardiac arrhythmias, this drug 
should be avoided.  Severe hypotension may be treated by 
transfusion, with whole blood or plasma expanders.  There is no 
known antidote.  

    A patient poisoned through inhalation of vinylidene chloride 
should be kept warm in a semi-prone position, in fresh air.  The 
airway should be kept clear and oxygen should be administered, if 

the subject is in a stupor or coma.  Artificial respiration should 
be provided, if necessary.  

    Following ingestion of vinylidene chloride, the mouth should be 
rinsed with water.  Vomiting should not be induced, because of the 
risk of aspiration of vinylidene chloride into the larynx and 
lungs.  Gastric lavage and/or the oral administration of activated 
charcoal or liquid paraffin may help to reduce the bioavailability 
of vinylidene chloride, if given within approximately 1 h of 
ingestion, and may prove of benefit up to 4 h after ingestion.  

    Eyes exposed to vinylidene chloride should be immediately 
irrigated with water for at least 15 minutes and medical advice 
should be sought.  

    In the case of dermal exposure, contaminated clothing should be 
removed and the affected area of skin washed with soap and water.  


    Vinylidene chloride was evaluated by WHO in 1984 [244] in the 
 Guidelines for drinking-water quality.  It was concluded that: 

    "Dichloroethenes have been detected in drinking-
    water, generally at levels less than 1 µg/litre.  
    The isomers have not always been differentiated.  
    1,1-dichloroethene is the isomer that causes most 
    concern because of evidence that it is carcinogenic 
    in experimental animals.  It is a chemical commonly 
    used in the synthesis of various polymers; for 
    example, food wrappers are often made of 1,1-
    dichloroethene co-polymers.  1,1-Dichloroethene 
    produces mammary tumours in both mice and rats, and 
    kidney adenocarcinomas in mice (13).  It has also 
    been shown to be mutagenic in the Ames assay.  A 
    linear multi-stage extrapolation model was applied 
    to data concerning the incidence of kidney 
    adenocarcinomas in Swiss mice in order to calculate 
    the recommended guideline value of 0.3 µg/litre." 

    Vinylidene chloride was evaluated by IARC Working Groups in 
1978 [85], 1985 [86], and 1987 [87].  In 1987, the following 
conclusions were reported: 


"A.  Evidence for carcinogenicity to humans ( inadequate) 
  In one epidemiological study of 138 US workers 
  exposed to vinylidene chloride, no excess of 
  cancer was found, but follow-up was incomplete, 
  and nearly 40% of the workers had less than 15 
  years' latency since first exposures.  In a study 
  in the Federal Republic of Germany of 629 workers 
  exposed to vinylidene chloride, seven deaths from 
  cancer (five bronchial carcinomas) were reported; 
  this number was not in excess of the expected 
  value.  Two cases of bronchial carcinoma were 
  found in workers, both of whom were 37 years old, 
  whereas 0.07 were expected for persons aged 35-39 
  years.  The limitations of these two studies do 
  not permit assessment of carcinogenicity of the 
  agent to humans.  No specific association was 
  found between exposure to vinylidene chloride and 
  the excess of lung cancer noted previously in a US 
  synthetic chemicals plant.  
"B.  Evidence for carcinogenicity to animals ( limited) 

  Vinylidene chloride was tested for carcinogenicity 
  in mice and rats by oral administration and by 
  inhalation, in mice by subcutaneous 
  administration and by topical application, and 
  in hamsters by inhalation.  Studies in mice and 
  rats by oral administration gave negative results.  
  In inhalation studies, no treatment-related 
  neoplasm was observed in rats or hamsters.  In 
  mice, a treatment-related increase in the 
  incidence of kidney adenocarcinomas was observed 
  in male mice, as were increases in the incidence 
  of mammary carcinomas in females and of pulmonary 
  adenomas in male and female mice.  In skin-painting 
  studies in female mice, vinylidene chloride 
  showed activity as an initiator, but, in a study 
  of repeated skin application, no skin tumour 
  occurred.  No tumour at the injection site was seen 
  in mice given repeated subcutaneous administrations.  

"C.  Other relevant data 
  "No data were available on the genetic and related 
  effects of vinylidene chloride in humans.  

  "Vinylidene chloride did not induce dominant lethal 
  mutations in mice or rats and did not induce 
  chromosomal aberrations in bone-marrow cells of 
  rats treated  in vivo ; however, it induced 
  unscheduled DNA synthesis in treated mice.  It did 
  not induce chromosomal aberrations or mutation in 
  Chinese hamster cells  in vitro but did induce 
  unscheduled DNA synthesis in rat hepatocytes.  
  Vinylidene chloride was mutagenic to plant cells 
  and induced mutation and gene conversion in yeast.  
  It was mutagenic to bacteria."

 1  ALTMAN, P.L.  & DITTMER, D.S.  (1966)  Environmental biology, 
    Bethesda, Maryland, Federation of American Societies for 
    Experimental Biology, pp.  326-328.  

 2  ANDERSEN, M.E.  & JENKINS, L.J., Jr (1977) Oral toxicity of 
    1,1-dichloroethylene in the rat: effects of sex, age and 
    fasting.   Environ.  Health Perspect.  21: 157-163.  

 3  ANDERSEN, M.E., JONES, R.A., & JENKINS, L.J., Jr (1977) 
    Enhancement of 1,1-dichloroethylene toxicity by pretreatment 
    of fasted male rats with 2,3-epoxy-propan-1-ol.   Drug Chem.  
     Toxicol., 1: 63-74.  

 4  ANDERSEN, M.E, JONES, R.A., & JENKINS, L.J., Jr (1978) The 
    acute toxicity of single, oral doses of 1,1-dichloroethylene 
    in the fasted, male rat: effect of induction and inhibition of 
    microsomal enzyme activities on mortality.   Toxicol.  appl.  
     Pharmacol., 46: 227-234.  

    JENKINS, L.J., Jr (1979a) Saturable metabolism and the acute 
    toxicity of 1,1-dichloroethene.   Toxicol.  appl.  Pharmacol., 47: 

    (1979b) The use of inhalation techniques to assess the kinetic 
    constants of 1,1-dichloroethylene metabolism.   Toxicol.  appl.  
     Pharmacol., 47: 395-409.  

    JENKINS, L.J., Jr (1980) The significance of multiple 
    detoxification pathways for reactive metabolites in the 
    toxicity of 1,1-dichloroethylene.   Toxicol.  appl.  Pharmacol, 52: 

 8  ANDERSON, D., HODGE, M.C.E., & PURCHASE, I.F.H.  (1977) 
    Dominant lethal studies with the halogenated olefins vinyl 
    chloride and vinylidene dichloride in male CD-1 mice.   Environ.  
     Health Perspect., 21: 71-78.  

 9  ATRI, F.R.  (1985) [Chlorinated compounds in the environment.] 
     Schriftenr.  Ver.  Wasser-Boden-Lufthyg., 60: 309-317 (in German) 

    SIMMON, V.F., & MAZZE, R.I.  (1976) Mutagenicity of volatile 
    anesthetics.   Anesthesiology, 45: 311-318.  

    R.I.  (1978) Fluroxene mutagenicity.   Mutat.  Res., 58: 183-191.  

 12 BADEN, J.M., KELLEY, M., & MAZZE, R.I.  (1982) Mutagenicity of 
    experimental inhalational anesthetic agents: sevofluorane, 
    synthane, dioxychlorane and dioxyfluorane.   Anesthesiology, 56: 
    (1986) Sequential dehalogenation of chlorinated ethenes.  
     Environ.  Sci.  Technol.,20, 96-99.  

    (1975) Tissue-mediated mutagenicity of vinylidene chloride and 
    2-chlorobutadiene in  Salmonella typhimurium.  Nature (Lond.), 
    255: 641-643.
    Mutagenic and alkylating metabolites of halo-ethylenes, 
    chloro-butadienes and dichlorobutenes produced by rodent or 
    human liver tissues.  Evidence for oxirane formation by P450-
    linked microsomal monooxygenases.   Arch.  Toxicol., 41: 249-277.  
 16 BATTELLE (1983)  Study of discharges of certain chloroethylenes 
     into the aquatic environment and the best technical means for 
     the reduction of water pollution from such discharges, Geneva, 
    Battelle Institute (Contract U/82/-176(537).  
 17 BELLAR, T.A., BUDDE, W.L., & EICHELBERGER, J.W.  (1979) The 
    identification and measurement of volatile organic compounds 
    in aqueous environmental samples.  In:  94th ACS Symposium 
     Series on Monitoring of Toxic Substances, Washington, DC, 
    American Chemical Society, pp.  49-62.  

 18 BIRKEL, T.J., ROACH, J.A.G., & SPHON, J.A.  (1977) 
    Determination of vinylidene chloride in saran films by 
    electron capture gas-solid chromatography and confirmation by 
    mass spectrometry.   J.  Assoc.  Off.  Anal.  Chem., 60: 1210-1213.  

    & DEL CARRATORE, R.  (1981) Genetic activity of vinylidene 
    chloride in yeast.   Mutat.  Res., 89: 179-185.  

    MILL, T., SAPIO, K.N., & SCHENDEL, D.E.  (1975)  Research 
     program on hazard priority ranking of priority chemicals.  
     Phase II: Final Report Menlo Park, California, Stanford 
    Research Institute (NSF-RA-E-75-190A; NTIS PB-263-161).  
 21 BUCCAFUSCO, R.J., ELLS, S.J., & LEBLANC, G.A.  (1981) Acute 
    toxicity of priority pollutants to bluegill (Lepomis 
    macrochirus).   Bull.  environ.  Contam.  Toxicol., 26: 446-452.  

 22 BUCKINGHAM, J., ed.  (1982)  Dictionary of organic compounds, 
    5th ed., New York, Chapman and Hall, Vol.  2, p.  1733.  

 23 CARLSON, G.P.  & FULLER, G.C.  (1972) Interaction of modifiers 
    of hepatic microsomal drug metabolism and the inhalation 
    toxicity of 1,1-dichloroethylene.   Res.  Commun.  chem.  Pathol.  
     Pharmacol., 4: 553-560.  

 24 CARPENTER, C.P., SMYTH, H.F., Jr, & POZZANI, U.C.  (1949) The 
    assay of acute vapor toxicity and the grading and 
    interpretation of results of 96 chemical compounds.   J.  ind.  
     Hyg.  Toxicol., 31: 343-346.  

 25 CEC (1988)  Draft proposal for a Council Directive on the 
     approximation of the laws of the Member States relating to 
     plastic materials and articles intended to come into contact 
     with foodstuffs, Brussels, Commission of the European 
    Communities, p.  43.  

 26 CERNA, M.  & KYPENOVA, H.  (1977) Mutagenic activity of 
    chloroethylenes analysed by screening system tests.   Mutat.  
     Res., 46: 214-215.  

 27 CHIECO, P., MOSLEN, M.T., & REYNOLDS, E.S.  (1981) Effect of 
    administrative vehicle on oral 1,1-dichloroethylene toxicity.  
     Toxicol.  appl.  Pharmacol., 57: 146-155.  

 28 CHIECO, P., MOSLEN, M.T., & REYNOLDS, E.S.  (1982) 
    Histochemical evidence that plasma and mitochondrial membranes 
    are primary foci of hepatocellular injury caused by 1,1-
    dichloroethylene.   Lab.  Invest., 46: 413-421.  

 29 CHIVERS, C.P.  (1972) Two cases of occupational leucoderma 
    following contact with hydroquinone monomethyl ether.   Br.  J.  
     ind.  Med., 29: 105-107.  

 30 COLE, R.H., FREDERICK, R.E., HEALY, R.P., & ROLAN, R.G.  (1984) 
    Preliminary findings of the priority pollutant monitoring 
    project of the nationwide urban runoff program.   J.  Water 
     Pollut.  Control Fed., 56: 898-908.  

 31 COMBA, M.E.  & KAISER, K.L.E.  (1983) Determination of volatile 
    contaminants at the ng.1-1 level in water by capillary gas 
    chromatography with electron capture detection.   Int.  J.  
     environ.  anal.  Chem., 16: 17-31.  

 32 COSTA, A.K.  & IVANETICH, K.M.  (1982) Vinylidene chloride: its 
    metabolism by hepatic microsomal cytochrome P-450  in vitro .  
     Biochem.  Pharmacol., 31: 2083-2092.  

 33 COSTA, A.K.  & IVANETICH, K.M.  (1984) Chlorinated ethylenes: 
    their metabolism and effect on DNA repair in rat hepatocytes.  
     Carcinogenesis, 5: 1629-1636.  

 34 CUPITT, L.T.  (1980)  Fate of toxic and hazardous materials in 
     the air, Washington, DC, US Environmental Protection Agency 
    (EPA 600/83-80-084; PB 80-221948).  

    J.V.  (1983) The uptake and disposition of 1,1-dichloroethylene 
    in rats during inhalation exposure.   Toxicol.  appl.  Pharmacol., 
    68: 140-151.  

    (1975/77) The acute toxicity of 47 industrial chemicals to 
    fresh and saltwater fishes.   J.  hazard.  Mater., 1: 303-318.  

    (1980) Rapid gas chromatographic method for the determination 
    of volatile and semivolatile organochlorine compounds in soil 
    and chemical waste disposal site samples.   J.  chromatogr.  Sci., 
    18: 85-88.  

 38 DEMERTZIS, P.G., KONTOMINAS, M.G., & GILBERT, S.G.  (1987) Gas 
    chromatographic determination of sorption isotherms of 
    vinylidene chloride n vinylidene chloride copolymers.   J.  Food.  
     Sci., 52 (3): 747-750.  

    (1980)  Toxicity of 1,1-dichloroethylene (vinylidene chloride) 
     to aquatic organisms, Midland, Michigan, Dow Chemical Company 
    (PB 81-111098).  

 40 DILLING, W.L.  (1977) Interphase transfer processes.  II.  
    Evaporation rates of chloromethanes, ethanes, ethylenes, 
    propanes and propylenes from dilute aqueous solution.  
    Comparison with theoretical predictions.   Environ.  Sci.  
     Technol., 11: 405-409.  

 41 DOW (1988)  Migration of vinylidene chloride monomer into food 
     simulating solvents from various vinylidene chloride 
     copolymers.  Report, Midland, Michigan, Dow Chemical Company, 
    p.  6.  

 42 DOWD, R.M.  (1985) EPA drinking-water proposals: round one.  
     Environ.  Sci.  Technol., 19: 1156.  

 43 DREVON, C.  & KUROKI, T.  (1979) Mutagenicity of vinyl chloride, 
    vinylidene chloride and chloroprene in V79 Chinese hamster 
    cells.   Mutat.  Res., 67: 173-182.  

 44 EASLEY, D.M., KLEOPFER, R.D., & CARASEA, A.M.  (1981) Gas 
    chromatographic-mass spectrometric determination of volatile 
    organic compounds in fish.   J.  Assoc.  Off.  Anal.  Chem., 64: 

 45 ECETOC (1985) Joint Assessment of Commodity Chemicals No.5:, 
     vinylidene chloride, Brussels, European Chemical Industry 
    Ecology and Toxicology Centre., 54 pp.  

 46 EISENREICH, S.J., LOONEY, B.B., & THORNTON, J.D.  (1981) 
    Airborne organic contaminants in the great lakes ecosystem.  
     Environ.  Sci.  Technol., 15: 30-38.  

 47 EUROCOP-COST (1976)  Analysis of organic micropollutants in 
     water, Luxembourg, Commission of the European Communities 
    (Cost Project 64b; EUCO/MDV/73/76, XII/476/76).  

    (1985) Volatile organic pollutants in biota and sediments of 
    Lake Pontchartrain.   Bull.  environ.  Contam.  Toxicol.  34: 

 49 FILSER, J.G.  & BOLT, H.M.  (1979) Pharmacokinetics of 
    halogenated ethylenes in rats.   Arch.  Toxicol., 42: 123-136.

 50 FOERST, D.  (1979) A sampling and analytical method for 
    vinylidene chloride in air.   Am.  Ind.  Hyg.  Assoc.  J., 40: 

 51 FOGEL, M.M., TADDEO, A.R., & FOGEL, S.  (1986) Biodegradation 
    of chlorinated ethenes by a methane-utilizing mixed culture.  
     Appl.  environ.  Microbiol., 51: 720-724.  

 52 FORKERT, P.G.  & REYNOLDS, E.S.  (1982) 1,1-dichloroethylene-
    induced pulmonary injury.   Exp.  lung Res., 3: 57-68.  

    (1985) Lung injury and repair: DNA synthesis following 1,1-
    dichloroethylene.   Toxicology, 36: 199-214.  

 54 FORKERT, P.G., HOFLEY, M., & RACZ, W.J.  (1986a) Metabolic 
    activation of 1,1-dichloroethylene by mouse lung and liver 
    microsomes.   Can.  J.  Physiol.  Pharmacol., 65: 1496-1499.  

 55 FORKERT, P.G., STRINGER, V., & RACZ, W.J.  (1986b) Effects of 
    administration of metabolic inducers and inhibitors on 
    pulmonary toxicity and covalent binding by 1,1-
    dichloroethylene in CD-1 mice.   Exp.  mol.  Pathol., 45: 44-58.  

 56 FORKERT, P.G., STRINGER, S., & TROUGHTON, K.M.  (1986c) 
    Pulmonary toxicity of 1,1-dichloroethylene correlation of 
    early changes with covalent binding.   Can.  J.  Physiol.  
     Pharmacol., 64: 112-121.  

 57 GAGE, J.C.  (1970) The subacute inhalation toxicity of 109 
    industrial chemicals.   Br.  J.  ind.  Med., 27: 1-18.  
 58 GAY, B.W., HANST, P.L., BUFALINI, J.J., & NOONAN, R.C.  (1976) 
    Atmospheric oxidation of chlorinated ethylenes.   Environ.  Sci.  
     Technol., 10: 58-67.  

 59 GIBBS, D.S.  & WESSLING, R.A.  (1983) Vinylidene chloride and 
    polyvinylidene chloride.  In: Mark, H.F., Othmer, D.F., 
    Overberger, C.G., & Seaborg, G.T., ed.   Kirk-Othmer 
     encyclopedia of chemical technology, 3rd ed., New York, John 
    Wiley and Sons, Vol.  23, pp.  764- 798.  

    (1980) Gas chromatographic determination of vinylidene 
    chloride monomer in packaging films and in foods.   J.  
     Chromatogr., 197: 71-78.  

    (1986) Production of vinylidene chloride from the thermal 
    decomposition of methyl chloroform.   Am.  Ind.  Hyg.  Assoc.  J., 
    47: 427-435.  

 62 GOING, J.E.  & SPIGARELLI, J.  (1977)  Environmental monitoring 
     near industrial sites - vinylidene chloride, Washington, DC, 
    US Environmental Protection Agency (EPA 560/6-77-026; NTIS PB- 

 63 GRASSELLI, J.R.  & RITCHEY, W.M., ed.  (1975) CRC  Atlas of 
     spectral data and physical constraints for organic compounds, 
    Cleveland, Ohio, CRC Press, Vol.  3.  

    D.  (1975) Mutagenicity  in vitro and potential carcinogenicity 
    of chlorinated ethylenes as a function of metabolic oxirane 
    formation.   Biochem.  Pharmacol., 24: 2013-2017.  

 65 GRIMSRUD, E.P.  & RASMUSSEN, R.A.  (1975) Survey and analysis of 
    halocarbons in the atmosphere by gas chromatography-mass 
    spectroscopy.   Atmos.  Environ., 9: 1014-1017.  

 66 GRONSBERG, E.S.  (1975) [Determination of vinylidene chloride 
    in the air.]  Gig.  i Sanit., 7: 77-79 (in Russian).  

 67 GUILLEMIN, C.L., MARTINEZ, R., & THIAULT, S.  (1979) Steam-
    modified gas-solid chromatography: a complementary technique 
    for organic pollutant survey.   J.  chromatogr.  Sci., 17: 677-681.  

 68 HARKOV, R., KEBBEKUS, B., BOZZELLI, J.W., & LIOY, P.J.  (1983) 
    Measurement of selected volatile organic compounds at three 
    locations in New Jersey during the summer season.   J.  Air 
     Pollut Control Assoc., 33: (12); 1177-1183.  

    DAISEY, J.  (1984) Comparison of selected volatile organic 
    compounds during the summer and winter at urban sites in New 
    Jersey.   Sci.  total Environ., 38: 259-274.  

    (1976) Increased "bile duct-pancreatic fluid" flow in 
    chlorinated hydrocarbon-treated rats.   Toxicol.  appl.  
     Pharmacol., 35: 41-49.  

    (1985) Tumour induction in several small fish species by 
    classical carcinogens and related compounds.  In:  Proceedings 
     of the Fifth Conference on Water Chlorination (Chemical, 
     Environmental Impact and Health Effects), pp.  429-438.  

    Acute toxicity of 54 industrial chemicals to sheepshead 
    minnows  (Cyprinodon variegatus).  Bull.  environ.  Contam.  
     Toxicol., 27: 596-604.  

 73 HENSCHLER, D.  (1977) Metabolism and mutagenicity of 
    halogenated olefins.  A comparison of structure and activity.  
     Environ.  Health Perspect., 21: 61-64.  

 74 HENSCHLER, D., BROSER, F., & HOPF, H.C.  (1970) ["Polyneuritis 
    cranialis" caused by poisoning with chlorinated acetylenes in 
    working with vinylidene chloride copolymers.]  Arch.  Toxicol., 
    26: 62-75 (in German).  

 75 HEWITT, W.R.  & PLAA, G.L.  (1983) Dose-dependent modification 
    of 1,1-dichloroethylene toxicity by acetone.   Toxicol.  Lett., 
    16: 145-152.  

 76 HIATT, M.H.  (1983) Determination of volatile organic compounds 
    in fish samples by vacuum distillation and fused silica 
    capillary gas chromatography/mass spectrometry.   Anal.  Chem., 
    55: 506-516.  

 77 HOFMANN, H.T.  & PEH, J.  (1976)  [Report on the test of 
     vinylidene chloride for mutagenic effects in Chinese Hamsters 
     after subacute inhalation,] Ludwigshafen, BASF 
    Aktiengesellschaft, 22 pp.  (in German).  

 78 HOLLIFIELD, H.C.  & MCNEAL, T.  (1978) Gas-solid chromatographic 
    determination of vinylidene chloride in saran film and three 
    simulating solvents.   J.  Assoc.  Off.  Anal.  Chem., 61: 537-544.  

    WOODS, J.S.  (1981) Follow-up study on the carcinogenicity of 
    vinyl chloride and vinylidene chloride in rats and mice: tumor 
    incidence and mortality subsequent to exposure.   J.  Toxicol.  
     environ.  Health, 7: 909-924.  

 80 HSE (1983)  Methods for the determination of hazardous 
     substances 28: Chlorinated hydrocarbon solvent vapours in air, 
    London, Health and Safety Executive.  

 81 HSE (1985)  Toxicity Review 13: Vinylidene chloride, London, 
    Health and Safety Executive, 59 pp.  

 82 HUBERMAN, E., BARTSCH, H., & SACHS, L.  (1975) Mutation 
    induction in Chinese hamster V79 cells by two vinyl chloride 
    metabolites, chloroethylene oxide and 2-chloroacetaldehyde.  
     Int.  J.  Cancer, 16: 639-644.  

 83 HULL, L.A., HISATSUNE, I.C., & HEICKLEN, J.  (1973) The 
    reaction of O3 with CCl2CH2.   Can.  J.  Chem., 51: 

 84 HUSHON, J.  & KORNREICH, M.  (1978)  Air pollution assessment of 
     vinylidene chloride, Washington, DC, US Environmental 
    Protection Agency (EPA 450/3-78-015) (Prepared by the Metrek 
    Division of the Mitre Corporation, McLean, Virginia; Contract 
    No.  68-02-1495).  

 85 IARC (1979)  Some monomers, plastics and synthetic elastomers, 
     acrolein, Lyons, International Agency for Research on Cancer, 
    pp.  439-459 (IARC Monograph on the Evaluation of the 
    Carcinogenic Risk of Chemicals to Humans, Vol.19).  

 86 IARC (1986)  Some chemicals used in plastics and elastomers: 
     vinylidene chloride, Lyons, International Agency for Research 
    on Cancer, pp.  195-226 (IARC Monographs on the Evaluation of 
    the Carcinogenic Risk of Chemicals to Humans, Vol.  39).  

 87 IARC (1987)  Overall evaluations of carcinogenicity: An 
     updating of IARC Monographs Vols.  1 - 42, Lyons, International 
    Agency for Research on Cancer, pp.  376-377 (IARC Monographs on 
    the Evaluation of Carcinogenic Risks to Humans, Supplement 7).  

 88 IRPTC (1988)  IRPTC Legal file, Geneva, International Register 
    of Potentially Toxic Chemicals, United Nations Environment 

 89 ISHIDATE, M., Jr, ed.  (1983)  The data book of chromosomal 
     tests in vitro on 587 chemical substances using a Chinese 
     hamster fibroblast cell line (Chl cells), Tokyo, The Realize 
    Inc., p.  582.  

 90 JACKSON, N.M.  & CONOLLY, R.B.  (1985) Acute nephrotoxicity of 
    1,1-dichloroethylene in the rat after inhalation exposure.  
     Toxicol.  Lett., 29: 191-199.  

 91 JAEGER, R.J.  (1975) Vinyl chloride monomer: comments on its 
    hepatotoxicity and interaction with 1,1-dichloroethylene.   Ann.  
     N.Y.  Acad.  Sci., 246: 150-151.  

 92 JAEGER, R.J.  & MURPHY, S.D.  (1973) Alterations of barbiturate 
    action following 1,1-dichloroethylene, corticosterone or 
    acrolein.   Arch.  int.  Pharmacodyn., 205: 281-292.  

 93 JAEGER, R.J., CONOLLY, R.B., & MURPHY, S.D.  (1973a) Diurnal 
    variation of hepatic glutathione concentration and its 
    correlation with 1,1-dichloroethylene inhalation toxicity in 
    rats.   Res.  Commun.  chem.  Pathol.  Pharmacol., 6: 465-471.  

 94 JAEGER, R.J., TRABULUS, M.J., & MURPHY, S.D.  (1973b) 
    Biochemical effects of 1,1-dichloroethylene in rats: 
    dissociation of its hepatotoxicity from a lipoperoxidative 
    mechanism.   Toxicol.  appl.  Pharmacol., 24: 457-467.  

 95 JAEGER, R.J., TRABULUS, M.J., & MURPHY, S.D.  (1973c) The 
    interaction of adrenalectomy, partial adrenal replacement 
    therapy, and starvation with hepatotoxicity and lethality of 
    1,1- dichloroethylene intoxication.   Toxicol.  appl.  Pharmacol., 
    25: 491 (Abstract No.  133).  

 96 JAEGER, R.J., CONOLLY, R.B., & MURPHY, S.D.  (1974) Effect of 
    18-hr fast and glutathione depletion on 1,1-dichloroethylene-
    induced hepatotoxicity and lethality in rats.   Exp.  mol.  
     Pathol., 20: 187-198.  

 97 JAEGER, R.J., SHONER, L.G., & COFFMAN, L.  (1977a) 
    1,1-Dichloroethylene hepatotoxicity: proposed mechanism of 
    action and distribution and binding of 14C radioactivity 
    following inhalation exposure in rats.   Environ.  Health 
     Perspect., 21: 113-119.  

 98 JAEGER, R.J., SZABO, S., & COFFMAN, L.J.  (1977b) 1,1-
    Dichloroethylene hepatotoxicity.  Effect of altered thyroid 
    funtion and evidence for the subcellular site of injury.   J.  
     Toxicol.  environ.  Health, 3: 545-555.  

 99 JENKINS, L.J., Jr & ANDERSEN, M.E.  (1978) 1,1-Dichloroethylene 
    nephrotoxicity in the rat.   Toxicol.  appl.  Pharmacol., 46: 

100 JENKINS, L.J., Jr, TRABULUS, M.J., & MURPHY, S.D.  (1972) 
    Biochemical effects of 1,1-dichloroethylene in rats: 
    comparison with carbon tetrachloride and 1,2-dichloroethylene.  
     Toxicol.  appl.  Pharmacol., 23: 501-510.  

101 JONES, B.K.  & HATHWAY, D.E.  (1978a) Tissue-mediated 
    mutagenicity of vinylidene chloride in  Salmonella typhimurium 
    TA1535.   Cancer Lett., 5: 1-6.  

102 JONES, B.K.  & HATHWAY, D.E.  (1978b) The biological fate of 
    vinylidene chloride in rats.   Chem.-biol.  Interact., 20: 27-41.  

103 JONES, B.K.  & HATHWAY, D.E.  (1978c) Differences in metabolism 
    of vinylidene chloride between mice and rats.   Br.  J.  Cancer, 
    37: 411- 417.  

104 KAISER, K.L.E., COMBA, M.E., & HUNEAULT, H.  (1983) Volatile 
    halocarbon contaminants in the Niagara River and in Lake 
    Ontario.   J.  Great Lakes Res., 9(2): 212-223.  

105 KANZ, M.F.  & REYNOLDS, E.S.  (1986) Early effects of 1,1-
    dichloroethylene on canalicular and plasma membranes: 
    ultrastructure and stereology.   Exp.  mol.  Pathol., 44: 93-110.  

    (1988) Potentiation of 1,1-dichloroethylene hepatotoxicity: 
    comparative effects of hyperthyreodism and fasting.   Toxicol.  
     appl.  Pharmacol., 95: 93-103.  

107 KIEZEL, L., LISZKA, M., & RUTKOWSKI, M.  (1975) [Gas 
    chromatographic determination of trace impurities in 
    distillates of vinyl chloride monomer.]  Chem.  Anal.  (Warsaw), 
    20: 555-562 (in Polish).  

108 KLIMISCH, J.H.  & FREISBERG, K.O.  (1979a)  [Report on the 
     determination of acute toxicity (LC50)  by inhalation of 
     vinylidene chloride in Chinese striped hamsters (fasting) 
     during a 4-hour exposure period.], Ludwigshafen, BASF 
    Aktiengesellschaft, 11 pp (in German).  

109 KLIMISCH, J.H.  & FREISBERG, K.O.  (1979b)  [Report on the 
     determination of acute toxicity (LC50)  by inhalation of 
     vinylidene chloride in Chinese striped hamsters (fed) during a 
     4-hour exposure period.], Ludwigshafen, BASF 
    Aktiengesellschaft, 14 pp (in German).  

    (1982) Investigation of the mortality of workers predominantly 
    exposed to vinylidene chloride.  In:  Proceedings of the 
     Medichem Congress, Paris, 1982.  

111 KRAMER, C.G.  & MUTCHLER, J.E.  (1972) The correlation of 
    clinical and environmental measurements for workers exposed to 
    vinyl chloride.   Am.  Ind.  Hyg.  Assoc.  J., 33: 19-30.  

112 KRIJGSHELD, K.R.  & GRAM, T.E.  (1984) Selective induction of 
    renal microsomal cytochrome P-450-linked monooxygenases by 
    1,1-dichloroethylene in mice.   Biochem.  Pharmacol., 33: 

    GINSBURG, E., & GRAM, T.E.  (1983) Lung-selective impairment of 
    cytochrome P-450-dependent monooxygenases and cellular injury 
    by 1,1-dichloroethylene in mice.   Biochem.  biophys.  Res.  
     Commun., 110: 675-681.  

114 LAIB, R.J., KELIN, K.P., KAUFMANN, I., & BOLT, H.M.  (1981) [On 
    the problem of carcinogenicity of vinylidene chloride 
    (1,1-dichloroethylene).] In: [ Epidemiological approaches in 
     occupational medicine], Stuttgart, Gentner Verlag, pp.  277-281 
    (in German).  

115 LAO, R.C., THOMAS, R.S., BASTIEN, P., HALMAN, R.A., & 
    LOCKWOOD, J.A.  (1982) Analysis of organic priority and non-
    priority pollutants in environmental samples by GC/MS/computer 
    systems.   Pergamon Ser.  environ.  Sci., 7: 107-118.  

116 LAZAREV, N.V., ed.  (1960) [Vinylidene chloride.] In: [ Harmful 
     substances in industry,] Leningrad, Chemia, pp.  215-216 (in 

117 LEBLANC, G.A.  (1980) Acute toxicity of priority pollutants to 
    water flea ( Daphnia magna).  Bull.  environ.  Contam.  Toxicol., 
    24: 684-691.  

    P.J., DIXON, R.L., & WOODS, J.S.  (1977) Inhalation toxicity of 
    vinyl chloride and vinylidene chloride.   Environ.  Health 
     Perspect., 21: 25-32.  

    R.L., & WOODS, J.S.  (1978) Carcinogenicity of vinyl chloride 
    and vinylidene chloride.   J.  Toxicol.  environ.  Health, 4: 15-30.  

120 LEIBMAN, K.C.  & ORTIZ, E.  (1977) Metabolism of halogenated 
    ethylenes.   Environ.  Health Perspect., 21: 91-97.  

121 LESAGE, S., PRIDDLE, M.W., & JACKSON, R.E.  (1988)  Organic 
     contaminants in ground water at the Gloucester landfill.  
     Report, National Water Research Institute, Burlington, 
    Ontario, p.13.  

122 LIEBLER, D.C.  & GUENGERICH, F.P.  (1983) Olefin oxidation by 
    cytochrome P-450: evidence for group migration in catalytic 
    intermediates formed with vinylidene chloride and trans-1-
    phenyl-1-butene.   Biochemistry, 22: 5482-5489.  

123 LIEBLER, D.C., MEREDITH, M.J., & GUENGERICH, F.P.  (1985) 
    Formation of glutathione conjugates by reactive metabolites of 
    vinylidene chloride in microsomes and isolated hepatocytes.  
     Cancer Res., 45: 186-193.  

124 LIEBLER, D.C., LATWESEN, D.G.  & REEDER, T.C.  (1988).  S-(2-
    chloroacetyl) glutathione, a reactive glutathione thiol ester 
    and a putative metabolite of 1,1-dichloroethylene.  
     Biochemistry, 27: 3652-3657.  
125 LIN, S.-N., FU, F.W.-Y., BRUCKNER, J.V., & FELDMAN, S.  (1982) 
    Quantitation of 1,1- and 1,2-dichloroethylene in body tissues 
    by purge-and-trap gas chromatography.   J.  Chromatogr., 244: 

126 LONG, R.M.  & MOORE, L.  (1987) Cytosolic calcium after carbon 
    tetrachloride, 1,1-dichloroethylene, and phenylephrine 
    exposure.  Studies in rat hepatocytes with phosphorylase  a 
    and quin 2.   Biochem.  Pharmacol., 36: 1215-122 

    (1981)  Aquatic fate process.  Data for organic priority 
     pollutants, Washington, DC, US Environmental Protection 
    Agency (EPA 440/4-81-014).  

128 MCCANN, J., SIMMON, V., STREITWIESER, D., & AMES, B.N.  (1975) 
    Mutagenicity of chloroacetaldehyde, a possible product of 1,2-
    dichloroethane (ethylene dichloride), chloroethanol (ethylene 
    chlorohydrin), vinyl chloride and cyclo-phosphamide.   Proc.  
     Natl Acad.  Sci.  (USA), 72: 3190-3193.  

    (1983) Evaluation of methylene chloride and vinylidene 
    chloride in mutational assays.   Environ.  Mutagen., 5: 426-427.  

130 MCDONALD, T.J., KENNICUTT, M.C., & BROOKS, J.M.  (1988) 
    Volatile organic compounds at a coastal Gulf of Mexico site.  
     Chemosphere, 17, 123-136.  

131 MCKENNA, M.J., WATANABE, P.G., & GEHRING, P.J.  (1977) 
    Pharmacokinetics of vinylidene chloride in the rat.   Environ.  
     Health Perspect., 21: 99-105.  
    (1978a) The pharmacokinetics of [14C]vinylidene chloride in 
    rats following inhalation exposure.   Toxicol.  appl.  Pharmacol., 
    45: 599-610.  

    GEHRING, P.J.  (1978b) Metabolism and pharmacokinetic profile 
    of vinylidene chloride in rats following oral administration.  
     Toxicol.  appl.  Pharmacol., 45: 821-835.  

    RAMPY, L.W.  (1982)  Vinylindene chloride: a chronic inhalation 
     toxicity and carcinogenicity study in rats.  Final Report, 
    Midland, Michigan, Dow Chemical, 100 pp.  

135 MAFF (1980)  Survey of vinylidene chloride levels in food 
     contact materials and in foods.  Third Report of the Steering 
     Group on Food Surveillance: Working Party on Vinylidene 
     Chloride, London, Ministry of Agriculture, Fisheries and Food, 
    23 pp (Food Surveillance Paper No.  3).  

    MONTESANO, R., CROISY, A., & JACQUIGNON, P.  (1975) 
    Mutagenicity of vinyl chloride, chloroethylene-oxide, 
    chloroacetylaldehyde and chloroethanol.   Biochem.  biophys.  Res.  
     Commun., 63: 363-370.  

137 MALAVEILLE, C., PLANCHE, G., & BARTSCH, H.  (1977) Factors for 
    efficiency of the  Salmonella microsome, mutagenicity assay.  
     Chem.-biol.  Interact., 17: 129-136.  

138 MALTONI, C.  & PATELLA, V.  (1983) Comparative acute toxicity of 
    vinylidene chloride.  The role of species, strain and sex.   Acta 
     oncol., 4: 239-256.  

139 MALTONI, C., COTTI, G., MORISI, L., & CHIECO, P.  (1977) 
    Carcinogenicity biosassays of vinylidene chloride.  Research 
    plan and early results.   Med.  Lav., 68: 241-262.  

140 MALTONI, C., CILIBERTI, A., & CARRETTI, D.  (1982) Experimental 
    contributions in identifying brain potential carcinogens in 
    the petro-chemical industry.   Ann.  N.Y.  Acad.  Sci., 381: 

141 MALTONI, C., COTTI, G., & CHIECO, P.  (1984) Chronic toxicity 
    and carcinogenicity bioassays of vinylidene chloride.   Acta 
     oncol., 5: 91-146.  
    V.  (1985) Experimental research on vinylidene chloride 
    carcinogenesis.  In: Maltoni, C.  & Mehlinan, M.A., ed.   Archives 
     of research in industrial carcinogenesis, Princeton, New 
    Jersey, Princeton Scientific Publishers, Vol.  3, p.95.  

143 MASUDA, Y.  & NAKAYAMA, N.  (1983) Protective action of 
    diethyldithiocarbamate and carbon disulfide against acute 
    toxicities induced by 1,1-dichloroethylene in mice.   Toxicol.  
     appl.  Pharmacol., 71: 42-53.  

144 MOTEGI, S., UEDA, K., TANAKA, H., & OHTA, M.  (1976) 
    Determination of residual vinylidene chloride monomer in 
    polyvinylidene chloride films used for fish jelly products.  
     Bull.  Jpn.  Soc.  Sci.  Fish., 42: 1387-1394.  

145 MOORE, L.  (1980) Inhibition of liver microsome calcium pump by 
     in vivo administration of CCl4, CHCl3 and 1,1-dichloroethylene 
    (vinylidene chloride).   Biochem.  Pharmacol., 29: 2505-2511.  

    B., & ZEIGER, E.  (1986)  Salmonella mutagenicity tests III.  
     Results from the testing of 270 chemicals, Environ.  Mutat., 
    8, (Suppl.  7): 1-119.  

147 MOSLEN, M.T.  & REYNOLDS, E.S.  (1985) Rapid, substrate-specific 
    and dose-dependent deactivation of liver cytosolic glutathione 
     S- transferases  in vivo by 1,1-dichloro-ethylene. Res.  Commun.  
     chem.  Pathol.  Pharmacol., 47: 59-72.  

148 MOSLEN, M.T., POISSON, L.R., & REYNOLDS, E.S.  (1985) 
    Cholestasis and increased biliary excretion of inulin in rats 
    given 1,1-dichloroethylene.   Toxicology, 34: 201-209.  

    (1979) Embryotoxicity and fetotoxicity of inhaled or ingested 
    vinylidene chloride in rats and rabbits.   Toxicol.  appl.  
     Pharmacol., 49: 189- 202.  

    (1977)  Market input/output studies.  Task 1: vinylidene 
     chloride, Washington, DC, US Environmental Protection Agency 
    (EPA 560/6-77-003; NTIS PB-273-205) (Prepared by Auerbach 
    Associates; Contract No.  68- 01-1996).  

    SCHWETZ, B.A.  (1983) A three-generation rat reproductive 
    toxicity study of vinylidene chloride in the drinking water.  
     Fundam.  appl.  Toxicol., 3: 75-79.  

152 NORRIS, J.M.  (1977) Toxicological and pharmacokinetic studies 
    on inhaled and ingested vinylidene chloride in laboratory 
    animals.  In:  Proceedings of the Technical Association of the 
     Pulp and Paper Industry (TAPPI) Paper Synthetics Conference, 
     Chicago, Illinois, 1977, Atlanta, Georgia, Technical 
    Association of the Pulp and Paper Industry, pp.  45-50.  

153 NORRIS, J.M.  & REITZ, R.H.  (1984)  Interpretative review of the 
     animal toxicological, pharmacokinetic/metabolism, biomolecular 
     and in vitro  mutagenicity studies on vinylidene chloride and 
     the significance of the findings for man, Midland, Michigan, 
    Dow Chemical Co., p.  24.  

154 NTP (1982)  Carcinogenesis bioassay of vinylidene chloride (CAS 
     No.  75-35-4) in F344 rats and B6C3F1 mice (gavage study), 
    Research Triangle Park, North Carolina, National Toxicology 
    Program (Technical Report Series No.  228; PB 82-258393).  

155 OBLAS, D.W., DUGGER, D.L., & LIEBERMAN, S.I.  (1980) The 
    determination of organic species in the telephone central 
    office ambient.   IEEE Trans.  Compnents Hybrids Manuf.  Technol., 
    CHMT-3 (1): 17-20.  

    & GLATT, H.R.  (1983) Vinylidene chloride: changes in drug 
    metabolising enzyme, mutagenicity and relation to its targets 
    for carcinogenesis.   Carcinogenesis, 4: 1031-1038.  

157 OKINE, L.K.N.  & GRAM, T.E.  (1986a) Tissue distribution and 
    covalent binding of [14C]1,1-dichloroethylene in mice.   In vivo 
    and  in vitro studies.   Adv.  exp.  Med.  Biol., 197: 903-910.  

158 OKINE, L.K.N.  & GRAM, T.E.  (1986b)  In vitro studies on the 
    metabolism and covalent binding of [14C]1,1-dichloroethylene 
    by mouse liver, kidney and lung.   Biochem.  Pharmacol., 35: 

159 OKINE, L.K.N., GOOCHEE, J.M., & GRAM, T.E.  (1985) Studies on 
    the distribution and covalent binding of 1,1-dichloroethylene 
    in the mouse.  Effects of various pretreatments on covalent 
    binding  in vivo.  Biochem.  Pharmacol., 34: 4051-4057.  

160 OSBOURNE, R.A.  (1964) Contact dermatitis caused by saran wrap.  
     J.  Am.  Med.  Assoc., 188: 1159.  

161 OTSON, R.  (1987) Purgeable organics in Great Lakes raw and 
    treated water.  Int.   J.  Environ.  anal.  Chem., 31: 41-53.  

162 OTSON, R.  & WILLIAMS, D.T.  (1982) Headspace chromatographic 
    determination of water pollutants.   Anal.  Chem., 54: 942-946.  

163 OTSON, R., WILLIAMS, D.T., & BIGGS, D.C.  (1982a) Relationships 
    between raw water quality, treatment and occurrence of 
    organics in Canadian potable water.   Bull.  environ.  Contam.  
     Toxicol., 28: 396-403.  

164 OTSON, R., WILLIAMS, D.T., & BOTHWELL, P.D.  (1982b) Volatile 
    organic compounds in water at thirty Canadian potable water 
    treatment facilities.   J.  Assoc.  Off.  Anal.  Chem., 65: 

165 OTT, M.G., LANGNER, R.R., & HOLDER, B.B.  (1975) Vinyl chloride 
    exposure in a controlled industrial environment.  A long-term 
    mortality experience in 594 employees.   Arch.  environ.  Health, 
    30: 333-339.  

    (1976) A health study of employees exposed to vinylidene 
    chloride.   J..  occup.  Med., 18: 735-738.  

167 PARSONS, F., WOOD, P.R., & DEMARCO, J.  (1984) Transformations 
    of tetrochloroethene and trichloroethene in microcosms and 
    groundwater.   J.  Am.  Water Works Assoc., February: 56-59.  

168 PATTERSON, J.W.  & KODUKALA, P.S.  (1981) Biodegradation of 
    hazardous organic pollutants.  CEP, April: 48-55.  

169 PEARSON, C.R.  & MCCONNELL, G.  (1975) Chlorinated C1 and C2 
    hydrocarbons in the marine environment. Proc.  R.  Soc.  Lond.  
    Ser.  B, 189: 305-332.  

170 PFAB, W., VON & MUCKE, G.  (1977) [On the migration of selected 
    monomers in foodstuffs and simulations.]  Dtsch.  Lebensm.  
     Rundschau, 73: 1-5 (in German).  

    M.P.M., & ZOETEMAN, B.C.J.  (1978) Determination of very 
    volatile halogenated organic compounds in water by means of 
    direct head-space analysis.   Anal.  Lett., A11(5): 437-448.  

172 PONOMARKOV, V.  & TOMATIS, L.  (1980) Long-term testing of 
    vinylidene chloride and chloroprene for carcinogenicity in 
    rats.   Oncology, 37: 136-141.  

    (1967) Effects on experimental animals of long-term inhalation 
    of trichloroethane, carbon tetrachloride, 1,1,1-trichloro-
    ethylene, dichlorodifluoromethane and 1,1-dichloroethylene.  
     Toxicol.  appl.  Pharmacol., 10: 270-289.  

174 PRICE, P.S.  (1985)  Volatile organochlorine compounds (VOC) 
     degradation.  Technical Memorandum, Washington, DC, US 
    Environmental Protection Agency, p.  19.  

    S.  (1986) Toxicokinetics and bioavailability of oral and 
    intravenous 1,1-dichloroethylene.   Fundam.  appl.  Toxicol., 6: 

    RAMPY, L.W., NORRIS, J.M., & GEHRING, P.J.  (1977) Results of 
    90-day toxicity study in rats given vinylidene chloride in 
    their drinking water or exposed to VDC vapour by inhalation.  
     Toxicol.  appl.  Pharmacol., 4: 187.  

    J.E, SCHWETZ, R.W., & NORRIS, J.M.  (1983) A chronic toxicity 
    and oncogenicity study in rats and subchronic toxicity study 
    in dogs on ingested vinylidene chloride.   Fundam.  appl.  
     Toxicol., 3: 55-62.  

178 QUAST, J.F., MCKENNA, M.J., RAMPY, L.W., & NORRIS, J.M.  (1986) 
    Chronic toxicity and oncogenicity study on inhaled vinylidene 
    chloride in rats.   Fundam.  appl.  Toxicol., 6: 105-144.  

    SCHWETZ, B.A.  (1977) Interim results of two-year toxicological 
    studies in rats of vinylidene chloride incorporated in the 
    drinking water or administered by repeated inhalation.  
     Environ.  Health Perspect., 21: 33-43.  

    SCHWETZ, B.A.  (1978) Results of two-year toxicological studies 
    in rats of vinylidene chloride incorporated in the drinking 
    water or administered by repeated inhalation.   Toxicol.  appl.  
     Pharmacol., 45: 244-245.  

181 RAMSTAD, T., NESTRICK, T.J., & PETERS, T.L.  (1981) 
    Applications of the purge-and-trap technique.   Am.  Lab., 13: 

182 RAY, P.  & MOORE, L.  (1982) 1,1-Dichloroethylene inhibition of 
    liver microsomal calcium pump  in vitro .  Arch.  Biochem.  
     Biophys., 218: 26-30.  

183 REICHERT, D., WERNER, H.W., & HENSCHLER, D.  (1978) Role of 
    liver glutathione in 1,1-dichloroethylene metabolism and 
    hepatotoxicity in intact rats and isolated perfused rat liver.  
     Arch.  Toxicol., 41: 169-178.  

    (1979) Molecular mechanism of 1,1-dichloroethylene toxicity: 
    excreted metabolites reveal different pathways of reactive 
    intermediates.   Arch.  Toxicol., 42: 159-169.  

185 REICHERT, D., SPENGLER, U ., ROMEN, W., & HENSCHLER, D.  (1984) 
    Carcinogenicity of dichloroacetylene: an inhalation study.  
     Carcinogenesis, 5: 1411-1420.  

    GEHRING, P.J.  (1980) Effects of vinylidene chloride on DNA 
    synthesis and DNA repair in the rat and mouse: a comparative 
    study with dimethylnitrosamine.   Toxicol.  appl.  Pharmacol., 52: 

187 REKKER, R.F.  (1977) The hydrophobic fragment constant, its 
    derivation and application.  A means of characterizing membrane 
    systems.  In: Nauta, W.Th.  & Rekker, R.F., ed.   Pharmacochemistry 
     library, Amsterdam, Elsevier Scientific Publishers, Vol.  1.  

    MURPHY, S.D.  (1975) Hepatotoxicity of vinyl chloride and 1,1-
    dichloroethylene.  Role of mixed function oxidase system.   Am.  
     J.  Pathol., 81: 219-236.  

189 REYNOLDS, E.S, MOSLEN, M.T., BOOR, P.J., & JAEGER, R.J.  (1980) 
    1,1-Dichloroethylene hepatotoxicity.  Time course of GSH 
    changes and biochemical aberrations.   Am.  J.  Pathol., 101: 

190 REYNOLDS, E.S., KANZ, M.F., CHIECO, P., & MOSLEN, M.T.  (1984) 
    1,1-Dichloroethylene: an apoptotic hepatotoxin.   Environ.  
     Health Perspect., 57: 313-320.  

191 RUSSELL, M.J.  (1975) Analysis of air pollutants using sampling 
    tubes and gas chromatography.   Environ.  Sci.  Technol., 9: 

192 RYLOVA, M.L.  (1953) [Toxicity of vinylidene chloride.]  Farmakol.  
     Toksikol., 16(1): 47-50 (in Russian).  

193 SASAKI, M., SUGIMURA, K., YOSHIDA, M.A., & ABE, S.  (1980) 
    Cytogenetic effects of 60 chemicals on cultured human and 
    Chinese hamster cells.   Kromosomo II,20: 574-584.  

194 SASSU, G.M, ZILIO-GRANDI, F., & CONTE, A.  (1968) Gas 
    chromatographic determination of impurities in vinyl 
    chloride.   J.  Chromatogr., 34: 394-398.  

195 SATO, A., NAKAJIMA, T., & KOYAMA, Y.  (1980) Effects of chronic 
    ethanol consumption on hepatic metabolism of aromatic and 
    chlorinated hydrocarbons in rats.   Br.  J.  ind.  Med., 37: 

196 SAWADA, M., SOFUNI, T., & ISHIDATE, M., Jr (1987) Cytogenetic 
    studies on 1,1-dichloroethylene and its two isomers in 
    mammalian cells  in vitro and  in vivo.  Mutat.  Res., 187: 

197 SAX, N.I.  (1984)  Dangerous properties of industrial materials, 
    6th ed., New York, Van Nostrand Reinhold, p.  2730.  

198 SCHMITZ, TH., THIESS, A.M., & PENNING, E.  (1979) [Inquiry into 
    morbidity among workers exposed to vinylidene chloride (VDC) 
    and polyvinylidene chloride (PVDC).] In: [ Report on the Tenth 
     Annual Meeting of the German Occupational Medicine Society 
     together with the Federation of Industrial Employers 
     Associations, Munster, 2-5 May, 1979, ] Stuttgart, Gentner 
    Verlag (in German).  

199 SEVERS, L.W.  & SKORY, L.K.  (1975) Monitoring personnel 
    exposure to vinyl chloride, vinylidene chloride and methyl 
    chloride in an industrial work environment.   Am.  Ind.  Hyg.  
     Assoc.  J., 39: 669-676.  

200 SHACKELFORD, W.M.  & KEITH, L.H.  (1976)  Frequency of organic 
     compounds identified in water, Washington, DC, US 
    Environmental Protection Agency, Office of Research and 
    Development, Environmental Research Laboratory (EPA 600/4-76-
    062; PB-265-470).  

201 SHELTON, L.G., HAMILTON, D.E., & FISACKERLY, R.H.  (1971) Vinyl 
    and vinylidene chloride.  In: Leonard, E.C., ed.   Vinyl and 
     diene monomers.  Part 3, New York, Wiley Interscience, 
    pp.  1505-1289.  

    B., UNGER, T., SAWYER, M., & LEE, C.C.  (1977a)  The 
     developmental toxicity of vinylidene chloride inhaled by rats 
     and mice during gestation, Washington, DC, US Environmental 
    Protection Agency (EPA 560/6-77-022; PB-281-713) (Prepared by 
    Midwest Research International, Kansas City, Missouri).  

203 SHORT, R.D., MINOR, J.L., WINSTON, J.M., & LEE, C.C.  (1977b) A 
    dominant lethal study in male rats after repeated exposures to 
    vinyl chloride or vinylidene chloride.   J.  Toxicol.  environ.  
     Health, 3: 965-968.  

    J., & LEE, C.C.  (1977c) Toxicity of vinylidene chloride in 
    mice and rats and its alteration by various treatments.   J.  
     Toxicol.  environ.  Health, 3: 913-921.  

205 SIDHU, K.S.  (1980) A gas-chromatographic method for the 
    determination of vinylidene chloride in air.   J.  anal.  
     Toxicol., 4: 266-268.  

206 SIEGEL, J., JONES, R.A., COON, R.A., & LYON, J.P.  (1971) 
    Effects on experimental animals of acute, repeated and 
    continuous inhalation exposures to dichloroacetylene mixtures.  
     Toxicol.  appl.  Pharmacol., 18: 168-174.  

207 SIEGERS, C.-P., YOUNES, M., & SCHMITT, G.  (1979) Effects of 
    dithiocarb and (+)-cyanidanol-3 on the hepatotoxicity and 
    metabolism of vinylidene chloride in rats.   Toxicology, 15: 

208 SIEGERS, C.-P., HEIDBUCHEL, K., & YOUNES, M.  (1983) Influence 
    of alcohol, dithiocarb, or (+)-catechin on the hepatotoxicity 
    and metabolism of vinylidene chloride in rats.   J.  appl.  
     Toxicol., 3: 90-95.  

209 SIEGERS, C.-P., HORN, W., & YOUNES, M.  (1985a) Effect of 
    hypoxia on the metabolism and hepatoxicity of carbon 
    tetrachloride and vinylidene chloride in rats.   Acta pharmacol.  
     toxicol., 56: 81-86.  

210 SIEGERS, C.-P., HORN, W., & YOUNES, M.  (1985b) Effect of 
    phorone-induced glutathione depletion on the metabolism and 
    hepatotoxicity of carbon tetrachloride and vinylidene 
    chloride.   J.  appl.  Toxicol., 5: 352-356.  

211 SILETCHNIK, L.M.  & CARLSON, G.P.  (1974) Cardiac sensitizing 
    effects of 1,1-dichloroethylene: enhancement by phenobarbital 
    pretreatment.   Arch.  int.  Pharmacodyn., 210: 359-364.  

212 SINGH, H.B., SALAS, L.J., SMITH, A.J., & SHIGEISHI, M.  (1981) 
    Measurements of some potentially hazardous organic chemicals 
    in urban environments.   Atmos.  Environ., 15: 601-612.  

213 SINGH, H.B., SALAS, L .J., & STILES, R.E.  (1982) Distribution 
    of selected gaseous organic mutagens and suspect carcinogens 
    in ambient air.   Environ.  Sci.  Technol., 16: 872-880.  

214 SPEIS, D.N.  (1980) Determination of purgeable organics in 
    sediments.   Environ.  Sci.  Res., 16: 201-206.  

215 SWEGER, D.M.  & TRAVIS, J.C.  (1979) An application of infrared 
    lasers to the selective detection of trace organic gases.  
     Appl.  Spectrosc., 33: 46-51.  

216 SZABO, S., JAEGER, R.J., MOSLEN, M.T., & REYNOLDS, E.S.  (1977) 
    Modification of 1,1-dichloroethylene hepatotoxicity by 
    hypothyroidism.   Toxicol.  appl.  Pharmacol., 42: 367-376.  

217 TABAK, H.H., QUAVE, S.A., ·MASHNI, C.I., & BARTH, E.F.  (1981) 
    Biodegradability studies with organic priority pollutant 
    compounds.   J.  Water Pollut.  Control Fed., 53: 1503-1518.  

218 TAN, S.  & OKADA, T.  (1979) Determination of residual 
    vinylidene chloride monomer in polyvinylidene chloride.  
    Hygienic studies on plastic containers and packages.  III.   J.  
     Food Hyg.  Soc.  Jpn, 20: 223-227.  

219 THIESS, A.M., FRENTZEL-BEYME, R., & PENNING, E.  (1979) 
    Mortality study of vinylidene chloride exposed persons.  In: 
    Heim, C.  & Kilian, D.J.., ed.   Proceedings of the 5th Medichem 
     Congress, San Francisco, September 1977, pp.  270-278.  

220 THOMPSON, J.A, HO, B., & MASTOVICH, S.L.  (1984) Reductive 
    metabolism of 1,1,1,2-tetrachloroethane and related chloro-
    ethanes by rat liver microsomes.   Chem-biol.  Interact., 51: 

221 TIERNEY, D.R., BLACKWOOD, T.R., & PIANA, M.R.  (1979)  Status 
     assessment of toxic chemicals: vinylidene chloride, 
    Cincinnati, Ohio, US Environmental Protection Agency (EPA 
    600/2-79-2100; PB 80- 146442).  

222 TORKELSON, T.R.  & ROWE, V.K.  ed.  (1982) Vinylidene chloride.  
    In: Clayton, G.D.  & Clayton, F.E.,  Patty's industrial hygiene 
     and toxicology, 3rd ed., New York, John Wiley and Sons, pp.  

223 US EPA (1984a) Method 601.  Guidelines establishing test 
    procedures for the analysis of pollutants under the Clean 
    Water Act (40 CFR 136).  Purgeable halocarbons.   Fed.  Reg., 49: 

224 US EPA (1984b) Method 1624, Revision B.  Guidelines 
    establishing test procedures for the analysis of pollutants 
    under the Clean Water Act (40 CFR 136).  Volatile organic 
    compounds by isotope dilution GC/MS.   Fed.  Reg., 49: 

225 US EPA (1985)  Health assessment document for vinylidene 
     chloride, Washington, DC, US Environmental Protection Agency, 
    Office of Health and Environmental Assessment (EPA 600/8-83-

226 US NIOSH (1987)  Manual of analytical methods, 3rd ed., 
    Cincinnati, Ohio, National Institute of Health and Human 
    Services, pp.1-3 (Method 1015).  

    A.C., MELCHIONNE, S., SEIDMAN, I., & ROTH, D.  (1979) 
    Carcinogenicity of halogenated olefinic and aliphatic 
    hydrocarbons in mice.   J.  Natl Cancer Inst., 63: 

228 VAN'T HOF, J.  & SCHAIRER, L.A.  (1982)  Tradescantia assay 
    system for gaseous mutagens.  A report of the US Environmental 
    Protection Agency Gene-Tox Program.   Mutat.  Res., 99: 

229 VIOLA, P.L.  & CAPUTO, A.  (1977) Carcinogenicity studies on 
    vinylidene chloride.   Environ.  Health Perspect., 21: 45-47.  

230 VOGEL, T.M.  & MCCARTY, P.L.  (1987) Abiotic and biotic 
    transformations of 1,1,1-trichloroethane under methanogenic 
    conditions.   Environ.  Sci.  Technol., 21: 1208-1213.  

231 WAKEHAM, S.G., GOODWIN, J.T., & DAVIS, A.C.  (1983) 
    Distributions and fate of volatile organic compounds in 
    Narragansett Bay, Rhode Island.   Can.  J.  Fish.  Aquat.  Sci., 40 
    (Suppl.2): 304-321.  

    (1985) Development of aquarium fish models for environmental 
    carcinogenesis: an intermittent-flow exposure system for 
    volatile, hydrophobic chemicals.   J.  appl.  Toxicol., 5: 

    WHITAKER, D., & PELLIZZARI, E.  (1982) Monitoring individual 
    exposure.  Measurements of volatile organic compounds in 
    breathing-zone air, drinking water and exhaled breath.  
     Environ.  Int., 8: 269-282.  

    ERICKSON, M., SPARACINO, C., & ZELON, H.  (1984) Personal 
    exposure to volatile organic compounds.  I.  Direct measurements 
    in breathing-zone air, drinking water, food, and exhaled 
    breath.   Environ.  Res., 35: 293- 319.  

    SPARACINO, C., & ZELON, H.  (1986) The total exposure 
    assessment methodology (TEAM) study: direct measurements of 
    personal exposures through air and water for 600 residents of 
    several US cities.  In: Cohen, Y., ed.   Pollutants in a 
     multimedia environment, New York, London, Plenum Publishing 
    Corporation.  pp.  289-315.  

236 WANG, T.  & LENAHAN, R.  (1984) Determination of volatile 
    halocarbons in water by purge-closed loop gas chromatography.  
     Bull.  environ.  Contam.  Toxicol., 32: 429-438.  

237 WANG, T., LENAHAN, R., & KANIK, M.  (1985) Impact of 
    trichloroethylene contaminated groundwater discharged to the 
    main canal and Indian river lagoon, Vero Beach, Florida.   Bull.  
     environ.  Contam.  Toxicol., 34: 578-586.  

    G., FOMINAYA, K., & SHERMA, J.  (1983)  Food additives 
     analytical manual, Arlington, Virginia, Association of 
    Official Analytical Chemists, Vol.  1, pp.  348-357.  

239 WASKELL, L.  (1978) Study of the mutagenicity of anesthetics 
    and their metabolites.   Mutat.  Res., 57: 141-153.  

240 WAXWEILER, R.J., SMITH, A.H., FALK, H., & TYROLER, H.A.  (1981) 
    Excess lung cancer risk in a synthetic chemicals plant.  
     Environ.  Health Perspect., 41: 159-165.  

241 WEAST, R.C., ed.  (1984)  CRC Handbook of chemistry and physics, 
    65th ed., Boca Raton, Florida, CRC Press, p.  C-295.  

242 WEGMAN, R.C.C., BANK, C.A., & GREVE, P.A.  (1981) Environmental 
    pollution by a chemical waste dump.   Stud.  environ.  Sci., 17: 

243 WESSLING, R.A.  & EDWARDS, F.G.  (1971) Vinylidene chloride 
    polymers.  In: Bikales, N.M., ed.   Encyclopedia of polymer 
     science and technology, New York, Wiley Interscience, Vol.  14, 
    pp.  540-579.  

244 WHO (1984)  Guidelines for drinking-water quality, Vol.  1 and 
    2, Geneva, World Health Organization.  

    M.V., & GUENGERICH, F.P.  (1985) Substrate specificity of human 
    liver cytochrome P-450 debrisoquine 4-hydroxylase probed using 
    immunochemical inhibition and chemical modeling.   Cancer Res., 
    45: 2116-2122.  

    P.A., & MIILLE, M.J.  (1981) Wastewater inputs and marine 
    bioaccumulation of priority pollutant organics off Southern 
    California; In: Jolley, R.L., Brungs, W.A., Cotrivo, J.A.  
    Cumming, R.B., Mattice, J.S., & Jacobs, V.A., ed.   Proceedings 
     of the Fourth Conference on Water Chlorination (Environmental 
     Impact and Health Effects), Pacific Grove, California, 18-23 
     October, 1981, Ann Arbor, Michigan, Ann Arbor Science 
    Publishers, Chapter 60, pp.  871-884.  

247 ZELLER, H.  & PEH, J.  (1975) [ Report on the tests of vinylidene 
     chloride for mutagenic effects in Chinese Hamsters after 
     single oral application (chromosomal study)], Ludwigshafen, 
    BASF Aktiengesellschaft, 12 pp (in German).  

248 ZELLER, H., KLIMISCH, J.H., & FREISBERG, K.O.  (1979a) [ Report 
     on the determination of acute toxicity (LC50) by inhalation of 
     vinylidene chloride in vapour form in Sprague-Dawley rats 
     (fasting) during a 4-hour exposure period], Ludwigshafen, BASF 
    Aktiengesellschaft, 14 pp (in German).  

249 ZELLER, H., KLIMISCH, J.H., & FREISBERG, K.O.  (1979b) [ Report 
     on the determination of acute toxicity (LC50) of vinylidene 
     chloride in Sprague-Dawley rats (fed) during a 4-hour exposure] 
    Ludwigshafen, BASF Aktiengesellschaft, 14 pp.  (in German).  

250 ZELLER, H., KLIMISCH, J.H., & FREISBERG, K.O.  (1979c) [ Report 
     on the determination of acute toxicity (LC50) by inhalation 
     of vinylidene chloride in NMRI mice (fasting) during a 4-hour 
     exposure] Ludwigshafen, BASF Aktiengesellschaft, 12 pp.  (in 

251 ZELLER, H., KLIMISCH, J.H., & FREISBERG, K.O.  (1979d) [ Report 
     on the determination of acute toxicity (LC50) by inhalation of 
     vinylidene chloride in NMRI mice (fed) during a 4-hour 
     exposure] Ludwigshafen, BASF Aktiengesellschaft, 12 pp.  (in 

1.  Résumé et conclusions

1.1 Propriétés, usages et méthodes d'analyse 

    Le chlorure de vinylidène (C2H2Cl2) est un liquide volatil et 
incolore d'odeur douceâtre.  On le stabilise au moyen de 
 p- méthoxyphénol afin d'éviter la formation de peroxydes explosifs.  
Le chlorure de vinylidène est utilisé pour la production de 
trichloro-1,1,1-éthane, de fibres et de copolymères modacryliques 
(avec du chlorure de vinyle ou de l'acrylonitrile).  On a mis au 
point des méthodes de chromatographie en phase gazeuse pour la 
recherche et le dosage du chlorure de vinylidène dans l'air, l'eau 
ou les emballages, les tissus de l'organisme, les denrées 
alimentaires et le sol.  Le détecteur le plus sensible est le 
détecteur à capture d'électrons.  

1.2 Sources et niveaux d'exposition 

    Chaque année on libère dans l'atmosphère une quantité de 
chlorure de vinylidène qui correspond à une proportion allant 
jusqu'à 5 % de la production totale (soit environ 23 000 tonnes au 
maximum).  La forte tension de vapeur et la faible solubilité dans 
l'eau de ce produit font qu'il est relativement abondant dans 
l'atmosphère par rapport aux autres compartiments du milieu.  On 
pense que le chlorure de vinylidène présent dans l'atmosphère a une 
demi-vie d'environ deux jours.  

    Dans l'eau, les concentrations sont très faibles.  Même dans les 
eaux résiduaires industrielles, les concentrations sont de l'ordre 
du µg/litre, c'est-à-dire bien inférieures aux concentrations 
toxiques pour la faune aquatique, concentrations qui sont de 
l'ordre du mg/litre.  Dans l'eau de boisson non traitée, les 
concentrations ne sont généralement pas décelables.  Dans l'eau 
potable traitée, la teneur en chlorure de vinylidène est 
généralement inférieure à 1 µg/litre encore qu'on ait trouvé des 
échantillons qui en contenaient 20 < g/litre.  Dans les denrées 
alimentaires, les concentrations ne sont généralement pas 
décelables, le maximum observé étant de 10 µg/kg.  

    L'exposition professionnelle au chlorure de vinylidène peut se 
produire soit par inhalation, soit par contamination de la peau ou 
des yeux.  Selon les pays, la dose maximale recommandée ou 
l'exposition moyenne pondérée en fonction du temps (TWA) se situent 
dans les limites de 8 à 500 mg/m3; quelquefois, la dose maximale 
correspond à la concentration la plus faible qui soit décelable de 
façon certaine.  Les limites d'exposition à court terme vont de 16 
à 80 mg/m3 et les valeurs plafond de 500 à 700 mg/m3.  

1.3 Absorption, distribution, métabolisme et excrétion 

    Le chlorure de vinylidène peut être absorbé facilement par les 
voies respiratoires ou digestives chez les mammifères; en revanche 
on de dispose pas de renseignements sur l'absorption percutanée.  

Administré à des rongeurs, le chlorure de vinylidène se répartit 
largement dans l'organisme de l'animal, les concentrations étant 
maximales dans le foie et les reins.  L'élimination par la voie 
pulmonaire du chlorure de vinylidène inchangé s'effectue selon un 
processus au moins biphasé qui dépend de la dose; elle est plus 
importante aux doses qui provoquent une saturation du métabolisme 
(c'est-à-dire 600 mg/m3 environ (150 ppm) chez le rat).  Des rats à 
qui l'on avait administré une dose de chlorure de vinylidène par 
voie orale et que l'on avait ensuite fait jeûner ont exhalé 
davantage de cette substance.  

    Les principales voies du métabolisme ont été identifiées chez 
le rat.  Dans la voie prédominante (phase I), intervient le 
cytochrome P-450 et il y a formation (vraisemblablement, mais pas 
forcément par l'intermédiaire d'un époxyde), d'acide 
monochloracétique.  Le chlorure de vinylidène peut stimuler 
l'activité du cytochrome P-450.  Un certain nombre de métabolites de 
la Phase I peuvent se conjuguer au glutathion ou à la phosphatidyl-
éthanolamine avant de subir d'autres transformations.  Le 
métabolisme est plus rapide chez la souris que chez le rat, avec un 
profil analogue où les dérivés conjugués au glutathion sont 
relativement plus abondants.  On a montré que le chlorure de 
vinylidène était également métabolisé par le cytochrome P-450 des 
microsomes humains.  

    Chez les rongeurs, le métabolisme du chlorure de vinylidène 
conduit à la déplétion du glutathion et à l'inhibition de la 
glutathion- S- transférase.  

1.4 Effets sur les animaux d'expérience et les systèmes 

1.4.1 Fixation aux tissus par liaison covalente 

    Le chlorure de vinylidène radio-marqué se fixe aux tissus 
hépatiques, rénaux et pulmonaires des rongeurs par liaison 
covalente et c'est ce phénomène qui déclenche le processus toxique.  
Les liaisons par covalence et par conséquent la toxicité sont 
accrues par la déplétion en glutathion et se produisent au niveau 
du foie et du rein à plus faible dose chez la souris que chez le 
rat.  Un certain nombre de métabolites du chlorure de vinylidène se 
fixent par liaison covalente aux thiols  in vitro .  

1.4.2 Toxicité aigue 

    Les estimations de la CL50 aiguë du chlorure de vinylidène 
varient considérablement, mais cette variation ne masque pas le 
fait que les souris sont beaucoup plus sensibles à cette substance 
que les rats ou les hamsters.  Les valeurs estimatives de la CL50 
orale à 4-h varient d'environ 8000 à 128 000 mg/m3 (2000-32 000 
ppm) chez le rat, de 450 à 820 mg/m3 (115-205 ppm) chez la souris et 
de 6640-11 780 mg/m3 (1660-2945 ppm) chez le hamster.  

    Du fait que la relation entre la concentration et la mortalité 
n'est pas linéaire, les estimations de la CL50 peuvent être 
entachées d'erreurs.  Chez toutes les espèces, la CL50 a tendance à 

être plus faible pour les mâles que pour les femelles et le jeûne 
(qui provoque une déplétion en glutathion) accroît la toxicité dans 
tous les cas.  Après administration par voie orale les valeurs de 
la DL50 s'établissaient approximativement à 1500 et 100 mh/kilo 
respectivement chez les rats et les souris.  Aprés inhalation, la 
toxicité s'est manifestée par une irritation des muqueuses, une 
dépression du système nerveux central et une cardiotoxicité 
progressive (bradycardie sinusale et arrythmies).  On a noté des 
lésions au niveau du foie, des reins et des poumons.  Chez les 
souris, qui sont plus sensibles que les rats à l'hépatotoxicité et 
à la néphrotoxicité du chlorure de vinylidène, on a constaté 
qu'une exposition à des concentrations ne dépassant pas 40 mg/m3 
(10 ppm) pendant 6 heures accroissait les lésions rénales et la 
réplication de l'ADN.  Comme dans le cas de l'inhalation, les 
principaux organes affectés par l'administration de chlorure de 
vinylidène par voie orale, sont le foie, les reins et les poumons.  
Le processus toxique au niveau du foie commence par des altérations 
au niveau des canaux biliaires et se poursuit par l'apparition de 
signes d'atteinte mitochondriale.  Après quoi il y a lésion du 
réticulum endoplasmique et mort de la cellule.  Il ne semble pas que 
la toxicité du chlorure de vinylidène pour le foie et le rein soit 
due à la peroxydation des lipides.  Il semblerait plutôt que 
l'augmentation de la concentration intra-cellulaire des ions 
calcium soit à l'origine de la toxicité de ce produit pour les 

    Les effets toxiques du chlorure de vinylidène dépendent, au 
moins partiellement, de l'activité du cytochrome P-450 (qui peut 
également intervenir dans le détoxication) et peuvent être 
exacerbés par une déplétion en glutathion.  L'éthanol et la 
thyroxine peuvent accroître l'hépatotoxicité; en revanche celle-ci 
est inhibée par le dithiorcarbe et la (+)-catéchine et modulée par 

1.4.3 Etudes à court terme 

    Des lésions hépatiques et rénales accompagnées, dans une 
moindre proportion, de lésions pulmonaires ont été observées chez 
des rongeurs exposés par inhalation à du chlorure de vinylidène à 
raison de 40 à 800 mg/m3, 4 à 8 heures par jour, pendant 4 jours ou 
plus par semaine.  Les souris se sont révélées plus sensibles que 
les rats, les cobayes, les lapins, les chiens et les saïmiris alors 
que chez les souris, la toxicité variait selon la souche utilisée.  
En général, les souris femelles étaient moins sensibles que mâles.  
On a observé une hépatotoxicité chez des rats et des souris exposés 
de façon intermittente à des concentrations de chlorure de 
vinylidène respectivement >800 mg/m3 (>200 ppm) ou égales à 220 
mg/m3 (55 ppm).  Pour induire une hépatotoxicité par exposition 
continue durant plusieurs jours, il fallait 240 mg/m3 (60 ppm) pour 
les rats et 60 mg/m3 (15 ppm) pour les souris.  Ce traitement 
intermittant ou continu a également provoqué une néphrotoxicité 
chez les souris.  Les souris mâles de la race Swiss se sont montrées 
particulièrement sensibles à la néphrotoxocité induite par le 
chlorure de vinylidène.  Les mâles n'ont pas survécu à une 
exposition continue de courte durée à 200 mg de chlorure de 

vinylidène par m3 (50 ppm).  Chez les chiens, les saïmiris et les 
rats, le seuil d'hépatotoxicité se situait à environ 80 mg/m3 (20 
ppm) administrés de façon continue sur 90 jours.  Des études à court 
terme (d'une durée d'environ 3 mois) au cours desquelles du 
chlorure de vinylidène a été administré par voie orale à des rats à 
des doses allant jusqu'à 20 mg/kg par jour et á des chiens à des 
doses allant jusqu'à 25 mg/kg, n'ont pas révélé de signes de 
toxicité, si ce n'est quelques lésions hépatiques infimes et 
réversibles chez les rats.  

1.4.4 Etudes à long terme 

    Des études à long terme comportant l'inhalation 
intermittente de chlorure de vinylidène ont révélé que la dose de 
300 mg/m3 (75 ppm) ne produisait que des modifications bénignes et 
réversibles au niveau du foie chez les rats.  A 600 mg/m3 
(150 ppm) c'est-à-dire la dose la plus forte qui soit supportable 
au cours d'une exposition à long terme, on constatait de nettes 
lésions hépatiques avec nécrose.  On a observé une forte mortalité 
avec des signes de lésion hépatique chez des souris soumises à une 
dose de 200 mg/m3 (50 ppm).  La néphrotoxicité était évidente 
chez la souris après un traitement à long terme à la dose de 100 
mg/m3 (25 ppm).  L'administration de chlorure de vinylidène par voie 
orale à des rats pendant un an à des doses quotidiennes allant 
jusqu'à 300 mg/kg n'a produit que de minimes anomalies hépatiques.  
Il n'est pas possible de tirer de ces données une valeur précise de 
la dose sans effet observable.  Une autre étude a révélé des signes 
d'inflammation rénale et de nécrose hépatique chez des rats et des 
souris soumis à une administration orale prolongée de chlorure de 
vinylidène à des doses quotidiennes respectives de 5 mg/kg et 2 

1.4.5 Génotoxicité et cancérogénicité 

    On a constaté que le chlorure de vinylidène était mutagène pour 
les bactéries et les levures, mais seulement en présence d'un 
système mammalien d'activation métabolique microsomique (S9).  Le 
composé a provoqué une synthèse anarchique de l'ADN dans des 
hépatocytes isolés de rats ainsi qu'une augmentation de la 
fréquence des échanges entre chromatides soeurs et des aberrations 
chromosomiques dans des cultures cellulaires additionnées de S9.  
Par contre, on n'a pas observé d'accroissement des mutations 
géniques chez les mammifères.  Il a été fait état d'une augmentation 
légère mais statistiquement significative de la liaison à l'ADN 
après exposition  in vivo .  Cette liaison était plus importante dans 
les cellules de souris que dans celles de rats et également plus 
importante dans les reins que dans le foie après une exposition de 
6 heures à des concentrations de 40 et 200 mg de chlorure de 
vinylidène/m3 (10 et 50 ppm).  En outre, le chlorure de vinylidène 
augmentait légèrement la synthèse anarchique de l'ADN dans le rein 
de la souris.  On a relevé aucun signe de mutation létale dominante 
ou d'effets cytogénétiques après exposition  in vivo de rongeurs, 
sauf dans le cas d'une étude au cours de laquelle on a observé des 
aberrations chromosomiques dans la moëlle osseuse de hamsters 

    Des études de cancérogénicité ont été effectuées sur trois 
espèces animales (rats, souris et hamsters).  Chez des souris mâles 
de race Swiss, on a relevé un net effet cancérogène (adénocarcinome 
rénal) après exposition prolongée intermittente à des 
concentrations de 100 ou de 200 mg/m3 de chlorure de vinylidène (25 
ou 50 ppm), mais pas aux concentrations de 0 ou 40 mg/m3 (0 ou 10 

    Il est possible que ces tumeurs rénales soient liées d'une 
manière ou d'une autre à la néphrotoxicité observée et que des 
atteintes rénales répétées puissent conduire directement à une 
réaction cancérogène selon un mécanisme non génotoxique ou qu'elles 
facilitent l'expression de l'activité génotoxique de certains 
métabolites chez cette espèce, pour ce sexe et au niveau de cet 
organe.  Toutefois, cette conclusion reste hypothétique du fait que 
les données disponibles sur les effets génétiques  in vivo sont 
limitées et que le chlorure de vinylidène a pu jouer le rôle 

    Dans la même étude, on a constaté une augmentation statistique 
de l'incidence des tumeurs pulmonaires (principalement des adénomes 
chez les souris des deux sexes) et des cancers mammaires (chez les 
femelles) mais on a pas observé de relation entre la dose et la 
réponse.  Chez des rats adultes exposés par inhalation au chlorure 
de vinylidène, on a signalé une légère augmentation des tumeurs 
mammaires sans relation avec la dose ainsi qu'une augmentation 
modérée des leucémies lorsque les rats étaient exposés à la 
substance in utero puis après leur naissance.  Il n'a pas été 
possible d'évaluer les résultats.  

1.4.6 Toxicité pour la fonction de reproduction 

    Aucun effet n'a été observé sur la fécondité de rats exposés en 
permanence à du chlorure de vinylidène (jusqu'à 200 mg/litre ou 200 
ppm) ajouté à leur eau de boisson.  Des rats et des souris qui 
avaient inhalé jusqu'à 1200 mg de chlorure de vinylidène par m3 
(300 ppm) pendant 22 à 23 heures, à différents stades de 
l'organogenèse, n'ont pas produit de foetus présentant des 
anomalies autres que celles qui peuvent être attribuées à une 
action toxique sur la mère.  

    Des rats et des lapins ont inhalé 7 h/jour 640 mg de chlorure 
de vinylidène par m3 (160 ppm) ou absorbé par voie orale environ 40 
mg/kilo de cette substance au cours des stades critiques de la 
gestation sans que les embryons ou les foetus présentent 
d'anomalies à ces doses, inférieures aux doses toxiques pour la 
mère.  Toutefois, des anomalies ont été constatées sur les embryons 
et les foetus aux doses toxiques pour la mère, comme l'a montré la 
réduction du gain de poids.  

1.5 Effets sur l'homme 

    Des concentrations de chlorure de vinylidène de l'ordre de 16 
000 mg/m3 (4000 ppm) provoquent une intoxication pouvant entraîner 
une perte de connaissance.  Additionné de stabilisateur, le chlorure 

de vinylidène est également irritant pour les voies respiratoires, 
les yeux et la peau.  A la suite d'expositions prolongées ou 
répétées à des doses infra-anesthésiques, on a signalé l'apparition 
de lésions rénales et hépatiques.  Il est difficile d'évaluer les 
résultats obtenus par les études épidémiologiques en raison de 
l'effectif limité des cohortes, d'une exposition simultanée au 
chlorure de vinyle et du fait qu'on n'a pas suffisamment tenu 
compte du tabagisme.  On n'a pas constaté d'augmentation 
statistiquement significative dans l'incidence des cancers chez les 
personnes exposées au chlorure de vinylidène, mais il est vrai que 
les études épidémiologiques présentaient des insuffisances; aussi 
n'est-il pas possible d'en conclure qu'il n'existe aucun risque de 
cancérogénicité.  On ne dispose d'aucun renseignement concernant les 
effets du chlorure de vinylidène sur la fonction de reproduction 

2.  Evaluation des effets sur l'environnement et des risques pour la 
santé humaine 

2.1 Evaluation des effets sur l'environnement 

    Par suite de la volatilité du chlorure de vinylidène, c'est 
l'atmosphère qui est le compartiment du milieu où il est le plus 
abondant.  La demi-vie du chlorure de vinylidène dans la troposphère 
est vraisemblablement d'environ deux jours, aussi ce composé ne 
contribue-t-il probablement pas à la réduction de la couche d'ozone 
stratosphérique.  Lessivage et volatilisation font du sol et des 
sédiments des compartiments où le chlorure de vinylidène n'est 
présent qu'en petites quantités et cet hydrocarbure chloré 
n'apparaît qu'en quantité minime dans le milieu aquatique du fait 
de sa volatilisation rapide.  On ignore si la dégradation de 
composés tel que le trichloréthylène et le perchloréthylène, 
souvent présents dans l'eau, contribuent de manière notable à la 
concentration du chlorure de vinylidène dans l'environnement.  

    La concentration du chlorure de vinylidène dans l'environnement 
et les valeurs de la toxicité aiguë pour les poissons et la daphnie 
montrent que les risques d'intoxication aiguë sont minimes pour la 
faune aquatique.  On ne dispose pas de données suffisantes sur la 
toxicité à long terme pour évaluer les effets sublétaux sur les 
organismes aquatiques qui vivent à proximité de sources 
relativement importantes de contamination par le chlorure de 
vinylidène, qu'il s'agisse d'eaux souterraines contaminées ou 
d'eaux résiduaires municipales ou industrielles.  

2.2 Evaluation des risques pour la santé humaine 

2.2.1 Niveau d'exposition 

    La population générale n'est exposée qu'à de très faibles 
teneurs de chlorure de vinylidène.  La concentration maximale qui 
ait été signalée dans l'eau de boisson est de 20 µg par litre, 
encore que l'exposition individuelle moyenne pour les citoyens des 
Etats-Unis d'Amérique par l'intermédiaire de l'eau de boisson soit 
estimée à moins de 0,01 µg par jour.  Il n'y a pas de chlorure de 

vinylidène en concentrations décelables dans les denrées 
alimentaires et en tout état de cause on n'a pas signalé de teneurs 
supérieures à 10 µg/kg.  On ignore quelles sont les concentrations 
dans les denrées alimentaires constituées d'organismes aquatiques 
mais elles sont vraisemblablement insignifiantes (section 10.1).  
Dans l'air ambiant on a signalé des concentrations en chlorure de 
vinylidène allant jusqu'à 52 µg/m3 (dans le périmètre d'une zone 
industrielle).  Des concentrations médianes dans l'air urbain de 20 
ng/m3 et de 8,7 µg/m3 ont été signalées aux Etats-Unis, 
respectivement dans des zones non industrielles et dans des zones 

    L'exposition professionnelle se produit notamment lors de la 
production et de la polymérisation du chlorure de vinylidène.  C'est 
principalement par la voie respiratoire que cette substance pénètre 
dans l'organisme et les limites maximales recommandées ou 
réglementées pendant une journée de travail vont de 8 à 500 mg/m3 
(ou la concentration la plus faible qui soit décelable par une 
méthode fiable), selon les pays.  Les limites d'exposition à court 
terme vont de 16 à 80 mg/m3 et les valeurs plafonds de 50 à 700 
mg/m3.  La concentration atmosphérique de chlorure de vinylidène en 
atmosphère confinée à laquelle certains travailleurs peuvent être 
exposés, ne dépasse pas 8 mg/m3.  

2.2.2  Effets aigus

    Chez l'homme, l'inhalation de fortes concentrations de chlorure 
de vinylidène (très approximativement, supérieures ou égales au 
seuil olfactif maximal de 4000 mg/m3) peuvent vraisemblablement 
provoquer une dépression du système nerveux central susceptible 
d'évoluer vers le coma.  En se basant sur la toxicité aiguë de ce 
composé chez l'animal, on pense que les effets toxiques du 
chlorure de vinylidène peuvent se manifester au niveau du foie, des 
reins ou des poumons bien en dessous du seuil olfactif minimum qui 
se situe aux environs de 2000 mg/m3.  L'exposition au chlorure de 
vinylidène peut provoquer une irritation des yeux, des voies 
respiratoires supérieures (à la concentration de 100 mg/m3 chez 
l'homme), et de la peau, encore que cet effet irritant soit, 
semble-t-il, dû en partie au para-méthoxyphénol utilisé comme 

    Chez la souris, qui est plus sensible que le rat aux effets 
hépatotoxiques et néphrotoxiques du chlorure de vinylidène, on a 
constaté une atteinte rénale après exposition à des concentrations 
ne dépassant pas 40 mg de chlorure de vinylidène par m3 (soit 10 
ppm) pendant 6 heures.  On a également observé une hépatotoxicité 
et une néphrotoxicité notables chez le rat.  Lorsque les animaux 
sont à jeun, ce qui a pour effet d'exacerber la toxicité, 
l'exposition au chlorure de vinylidène à des teneurs de 600 mg/m3 
(150 ppm) et de 800 mg/m3 (200 ppm) pendant 6 heures a provoqué 
chez le rat des effets toxiques, respectivement au niveau du foie 
et du rein.  Des études sur le rat ont montré que l'ingestion 
d'alcool avant l'exposition peut stimuler le métabolisme et 
exacerber la toxicité du chlorure de vinylidène.  La toxicité agiuë 
dépend de l'espèce, du sexe, de la souche et de l'état alimentaire 

de l'animal.  Chez le rat et la souris, les différences de 
sensibilité interspécifiques sont liées à l'activité du métabolisme 
oxydatif.  S'il n'est pas possible de déterminer qui du rat ou de 
la souris constitue le meilleur modèle pour l'être humain, toujours 
est-il que le métabolisme des microsomes hépatiques est, chez 
l'homme, quantitativement analogue à celui du rat, espèce 
relativement peu sensible aux effets du chlorure de vinylidène.  
Rien n'indique qu'il existe une différence de nature entre l'homme 
et les rongeurs pour ce qui est du métabolisme oxidatif du chlorure 
de vinylidène.  

    Il semblerait que la marge entre la concentration toxique chez 
l'animal (40 mg/m3 pour la souris) et les limites d'exposition 
professionnelle fixées par certains pays puisse être insuffisante, 
voire nulle.  

2.2.3  Effets à long terme et génotoxicité

    Une exposition prolongée ou des expositions de courte durée 
répétées à des doses infra-anesthésiques peuvent provoquer des 
lésions rénales ou hépatiques.  Sur la base d'études à long terme 
chez l'animal, dans des conditions reproduisant une exposition 
professionnelle, on a observé chez le rat, des altérations au 
niveau du foie à une dose de 300 mg/m3 (75 ppm).  Chez la souris, 
des lésions rénales et hépatiques ont été observées respectivement 
à 100 mg/m3 (25 ppm) et 200 mg/m3 (50 ppm).  La sensibilité aux 
effets toxiques observée au cours des différentes études présente 
des variations considérables.  

    Le chlorure de vinylidène n'affecte pas, semble-t-il, la 
capacité de reproduction chez l'animal et ne semble pas non plus 
comporter de risques d'embryotoxicité ou de tératogénicité aux 
doses inférieures à celles qui seraient toxiques pour la mère, mais 
on n'a pas effectué d'études de ce type chez l'homme.  Aux doses 
toxiques pour la mère-à en juger par une réduction du gain de 
poids-on a observé des effets toxiques sur l'embryon et le foetus 
et des anomalies foetales.  

    Le chlorure de vinylidène est mutagène pour les bactéries et 
les levures en présence d'un système métabolique de mammifère.  
Certaines cellules mammaliennes se révèlent également sensibles  in 
 vitro aux effets mutagènes et aux lésions de l'ADN.  La plupart des 
études  in vivo effectuées sur des rats n'ont pas permis d'observer 
d'effets génotoxiques manifestes, à en juger par les tests de 
létalité dominante et certains critères cytogénétiques mais on a 
tout de même signalé la présence d'aberrations chromosomiques dans 
les cellules de la moelle osseuse de hamsters chinois.  La liaison 
à l'ADN et sa réparation sont décelables  in vivo chez les rongeurs 
mais en proportion minime.  Les études génétiques  in vivo incitent 
donc à penser qu'il existe une certaine toxicité génique mais, dans 
la majorité des cas, il s'agit d'effets non décelables ou minimes.  

    Plusieurs épreuves de cancérogénicité ont été effectuées sur 
trois espèces d'animaux d'expérience (souris, rats et hamsters) 
selon différentes voies d'administration.  Malheureusement, la 

plupart de ces études laissent beaucoup à désirer tant au niveau de 
leur conception que de l'évaluation du risque cancérogène.  Aucun 
effet cancérogène significatif n'a été observé chez des rats qui 
recevaient ce composé par la voie orale.  Chez des rats adultes 
exposés par inhalation, on a signalé une augmentation de la 
fréquence des tumeurs mammaires qui n'était toutefois pas liée à la 
dose.  Une légère augmentation de la fréquence des leucémies a été 
également observée, lorsque les rats étaient exposés in utero ou 
après leur naissance.  Ces observations n'ont pas pu être évaluées.  
Lors d'une étude sur la souris, on a observé chez les mâles une 
augmentation de l'incidence des adénocarcinome du rein aux doses 
de 200 et 100 mg/m3 (50 et 25 ppm), mais aucun effet de ce genre 
aux doses de 40 et 0 mg/m3 (10 et 0 ppm).  Au cours de la même 
étude, une augmentation statistiquement significative de 
l'incidence des tumeurs pulmonaires (essentiellement des adénomes 
chez les deux sexes) et des carcinomes mammaires (chez les 
femelles) a été observée, sans toutefois qu'il y ait de relation 

    Il est possible que ces tumeurs rénales soient liées d'une 
manière ou d'une autre à la néphrotoxicité observée et que des 
atteintes rénales répétées puissent conduire directement à une 
réaction cancérogène selon un mécanisme non-génotoxique ou qu'elle 
facilite l'expression de l'activité génotoxique de certains 
métabolites chez cette espèce, pour ce sexe et au niveau de cet 
organe.  Toutefois, cette conclusion reste hypothétique du fait que 
l'on ne possède pas suffisamment de résultats sur la relation dose-
réponse pour ce qui est des effets génétiques  in vivo; en outre, le 
chlorure de vinylidène a pu jouer le rôle d'initiateur lors d'un 
test cutané en deux phases sur la souris.  

    Les études épidémiologiques ne fournissent pas de résultats 
statistiquement significatifs qui puissent permettre de conclure à 
un accroissement du risque de cancer à la suite d'une exposition 
professionnelle au chlorure de vinylidène, toutefois ces études 
présentent des insuffisances telles qu'on ne peut procéder à une 
évaluation convenable du risque de cancérogénicité pour l'homme.  

    Même si les estimations effectuées par divers auteurs écartent 
l'idée d'une surmortalité par cancer en arguant qu'il s'agit d'une 
pure coincidence(en raison du petit nombre de cas et du faible 
effectif des cohortes), il n'est pas inutile de préciser que les 
résultats obtenus sont systématiquement supérieurs aux prévisions.  
Ainsi, dans les deux études de cohorte dont il est fait état, on a 
observé un cancer du poumon dans 7 cas, alors qu'on aurait dû avoir 
3,16 décès.  On ne peut pas écarter ce résultat, mais il ne faut pas 
oublier l'existence, dans une étude, d'une exposition concomitante 
au chlorure de vinylidène.  Etant donné que les cohortes ont été 
constituées sur la base d'une exposition au chlorure de vinylidène, 
on peut se trouver dans l'impossibilité d'éliminer d'autres 
expositions parasites.  

    Les données de morbidité indiquées (y compris un cas de cancer 
du testicule) ne sont pas dénuées d'intérêt.  Selon les auteurs, la 
forte morbidité hépatique serait imputable à la consommation 

d'alcool.  Cette hypothèse ne tient pas, puisque la consommation 
d'alcool de l'ensemble des personnes étudiées (pas seulement les 
cas identifiés) n'a pas été évaluée.  

3.  Recommandations 

3.1 Recommandations en vue de travaux futurs 

    Il faudrait disposer d'une meilleure estimation de la production 
annuelle mondiale de chlorure de vinylidène ainsi que des quantités 
de cette substance qui pénètrent dans l'environnement à partir de 
l'ensemble des sources de pollution, que le composé soit libéré tel 
quel ou qu'il résulte de la décomposition d'autres produits 

    Les prévisions relatives à sa destiné dans l'environnement 
reposent sur un nombre limité de données expérimentales.  Il 
faudrait de nouvelles données sur les produits de dégradation et de 
transformation de ce composé dans l'air, le sol, l'eau et les 
sédiments ainsi que sur son métabolisme chez des espèces non-
mammaliennes représentatives.  

    Il conviendrait d'effectuer des études de toxicité à long terme 
chez diverses espèces aquatiques représentatives (poissons, 
crustacés et mollusques), selon divers critères pathologiques.  

    Il faut également définir de manière plus précise, afin 
d'établir des critères de sécurité en matière d'exposition, quels 
sont, chez l'animal et chez l'homme, les mécanismes des effets 
toxiques résultant d'une exposition de brève ou prolongée au 
chlorure de vinylidène.  

    Il faudrait exploiter de manière plus complète les données 
existantes sur la cancérogénicité.  Si l'on envisage d'autres études 
de cancérogénicité, elles devront être menées selon un protocole 
expérimental reconnu, pendant toute l'existence des sujets, ce 
protocole étant conçu de manière à tenir compte des propriétés 
particulières du chlorure de vinylidène.  Ces études doivent 
notamment prendre en considération la courte demi-vie du produit 
dans l'organisme, l'importance de l'âge au début de l'exposition, 
la durée de l'exposition quotidienne et autres données susceptibles 
d'aider à la détermination des doses à administrer.  Les espèces et 
les souches d'animaux de laboratoire devront être soigneusement 
sélectionnées.  Il serait également très utile de disposer de 
données de toxicité ainsi que de données métaboliques et pharmaco- 
cinétiques sur ces animaux.  

    Il faudrait effectuer des études longitudinales à long terme 
sur la morbidité et la mortalité au sein de populations prises au 
hasard et qui sont exposées au chlorure de vinylidène.  

    Des études épidémiologiques sont nécessaires pour permettre 
l'évaluation des effets de l'exposition au chlorure de vinylidène 
(notamment une exposition prolongée à de faibles doses) dans les 
populations humaines.  Il est tout particulièrement important de 

disposer de données sur des effets tels que les affections 
cérébrovasculaires prématurées et le cancer.  En outre, les études 
qui seront effectuées devront tenir dûment compte de facteurs de 
confusion tels que le tabagisme et la consommation d'alcool 
(éventuellement selon un système cas/témoin).  

    Afin d'apprécier l'effet de l'action réglementaire menée au 
cours des dernières années, il conviendrait de confronter les 
résultats des études en cours aux données rétrospectives.  

    Pour résoudre le problème que posent les faibles effectifs du 
personnel sur les lieux de production, on pourrait, pour les 
investigations en cours comme pour les investigations futures, 
recourir à des études multicentriques avec regroupement des 
données.  Il faudra également étudier sur l'animal d'expérience si 
la  N- acétylcystéine, un agent sulfhydrilé présente un intérêt 
pour le traitement des intoxications par le chlorure de vinylidène.  

    Il est nécessaire de comparer la pharmacocinétique et le 
métabolisme du chlorure de vinylidène tant  in vivo qu' in vitro 
spécialement au niveau du rein, du foie et des poumons chez 
diverses espèces d'animaux d'expérience et chez l'homme, afin de 
pouvoir mieux interpréter les résultats fournis par les études de 
toxicité  in vivo. Il faut également obtenir des données sur la 
génotoxicité potentielle du chlorure de vinylidène au site de la 
cancérogénèse, parallèlement sur plusieurs espèces, afin de voir si 
un mécanisme génétique est en cause.  

    Compte tenu des observations neurotoxicologiques dont il est 
fait état dans la présente analyse, il paraît nécessaire d'étudier 
le rôle des systèmes de modulation dans la pathogénèse de 
l'intoxication par le chlorure de vinylidène.  

3.2 Protection personnelle et traitement des intoxications 

3.2.1 Protection personnelle 

    Dans l'industrie, où peuvent se produire des expositions de 
brèves durées par inhalation au dessus des limites recommandées, il 
conviendrait d'utiliser des masques faciaux avec cartouche 
filtrante pour se protéger des vapeurs organiques et, si nécessaire 
en cas d'urgence, des masques respiratoires avec arrivée d'air.  Les 
personnes qui manipulent du chlorure de vinylidène devront porter 
des vêtements protecteurs ainsi que des lunettes spéciales; cet 
équipement devra être correctement entretenu afin de protéger le 
corps contre tout contact.  Dans les ateliers, on assurera une 
ventilation permanente et l'on disposera des grilles d'aération 
munies de filtres là où des déversements accidentels ou des fuites 
risquent de se produire.  Il est recommandé de surveiller les 
émissions de chlorure de vinylidène au cours des opérations de 
remplissage.  En cas de fuite, on procédera à l'évaporation directe 
du produit s'il s'agit d'une fuite mineure ou à son évaporation 
controlée en présence d'une mousse synthétique s'il s'agit d'une 
fuite plus importante.  On pourra disperser la vapeur de chlorure de 
vinylidène à partir de cette mousse par pulvérisation d'eau.  

3.2.2 Traitement des intoxications humaines 

    En cas d'exposition excessive ou d'ingestion, il faut 
s'adresser à un médecin.  Il faut veiller particulièrement aux 
poumons, à la peau et aux yeux du fait des propriétés irritantes du 
chlorure de vinylidène.  Il importe de surveiller les fonctions 
cardiaque, hépatique et rénale ainsi que le système nerveux 
central.  Les données obtenues sur l'animal d'expérience montrent 
que le chlorure de vinylidène accroît notablement la sensibilité 
aux arythmies cardiaques induites par l'adrénaline, de sorte que ce 
produit est à éviter.  En cas d'hypotension grave, on pourra 
procéder à une transfusion de sang total ou d'un succédané du 
plasma.  Il n'existe aucun antidote.  

    En cas d'intoxication par inhalation de chlorure de vinylidène, 
il faut maintenir le malade à l'air libre en semi-décubitus 
ventral.  On dégagera les voies aériennes et l'on placera le malade 
sous oxygène en cas de stupeur ou de coma.  Si nécessaire, on 
procédera à la respiration artificielle.  

    En cas d'ingestion de chlorure de vinylidène, rincer la bouche 
avec de l'eau.  Ne pas faire vomir le malade car il y a risque 
d'aspiration du chlorure de vinylidène dans le larynx et les 
poumons.  Un lavage d'estomac ou l'administration par voie orale de 
charbon actif ou de paraffine liquide peut contribuer à réduire la 
biodisponibilité du chlorure de vinylidène si on procède à ce 
traitement dans l'heure qui suit l'ingestion, l'effet bénéfique 
étant encore sensible aprés 4 heures.  

    Si les yeux ont été atteints par du chlorure de vinylidène, les 
rincer immédiatement à l'eau pendant plus de 15 minutes et 
consulter un médecin.  

    En cas d'exposition cutanée, ôter les vêtements souillés et 
laver la peau à l'eau et au savon.  


1.  Resumen y conclusiones 

1.1.  Propiedades, usos y métodos analíticos

    El cloruro de vinilideno (C2H2Cl2) es un líquido volátil e 
incoloro con un olor dulzón.  Se estabiliza con  p- metoxifenol para 
impedir la formación de peróxidos explosivos.  El cloruro de 
vinilideno se usa para producir 1,1,1-tricloroetano y para formar 
fibras modacrílicas y copolímeros (con cloruro de vinilo o 
acrilonitrilo).  Se han puesto a punto métodos de cromatografía de 
gases para analizar el cloruro de vinilideno en el aire, el agua, 
las películas para envoltorios, los tejidos orgánicos, los 
alimentos y el suelo.  El método más sensible de detección es la 
captura electrónica.  

1.2.  Fuentes y niveles de exposición 

    Todos los años ingresa en la atmósfera alrededor del 5% del 
cloruro de vinilideno producido (que representa un máximo cercano a 
23 000 toneladas).  La elevada presión de vapor y la baja 
solubilidad en agua favorecen concentraciones atmosféricas 
relativamente elevadas en comparación con otros "compartimentos" 
ambientales.  Se cree que el cloruro de vinilideno tiene una 
semivida en la atmósfera de aproximadamente dos días.  

    Los niveles ambientales en el agua son sumamente bajos.  Incluso 
en aguas residuales industriales sin tratar, las concentraciones 
pasan raras veces del orden de los µg/litro, lo que está muy por 
debajo del margen de mg/litro de toxicidad para los organismos 
acuáticos.  Los niveles en el agua de bebida sin tratar no suelen 
ser detectables.  En las aguas potables tratadas, se ha encontrado 
que el nivel de cloruro de vinilideno suele ser < de 1 µg/litro, 
si bien se han encontrado muestras que contienen hasta 20 µg/litro.  
Los niveles de cloruro de vinilideno en los alimentos normalmente 
no son detectables, siendo la concentración máxima observada de 10 

    La exposición profesional al cloruro de vinilideno se da 
principialmente por inhalación, aunque también puede producirse 
contaminación por la piel o los ojos.  Según los países, el límite 
de exposición máximo recomendado o promedio ponderado en función 
del tiempo se encuentra entre 8 y 500 mg/m3, o es la concentración 
más baja detectable con cierto margen de confianza.  Los límites de 
exposición a corto plazo varían entre 16 y 80 mg/m3 y los valores 
máximos varían entre 50 y 700 mg/m3.  

1.3.  Absorción, distribución, metabolismo y excreción 

    El cloruro de vinilideno puede absorberse rápidamente por la 
vía respiratoria y oral en mamíferos; no se dispone de datos sobre 
la absorción cutánea.  El cloruro de vinilideno se distribuye por 
todo el organismo del roedor y alcanza concentraciones máximas en 
el hígado y el riñón.  La eliminación pulmonar de cloruro de 

vinilideno sin modificar es cuando menos bifásica y dependiente de 
la dosis, siendo de mayor importancia en el caso de dosis que 
saturan el metabolismo (>unos 600 mg/m3 (<150 ppm) por inhalación 
en la rata).  En la rata sometida a ayuno se observó una reducción 
en el metabolismo de la dosis oral y un nivel consiguiente mayor de 
cloruro de vinilideno exhalado.  

    Se han caracterizado las principales vías metabólicas en la 
rata.  El metabolismo predominante de la fase I entraña la 
participación del citocromo P-450 y la formación (posible pero no 
necesariamente por medio de un epóxido) de ácido monocloroacético.  
El cloruro de vinilideno puede inducir actividad de citocromo P-
450.  Varios metabolitos de la fase I se conjugan con glutatión y/o 
con fosfatidil etanolamina antes de sufrir ulteriores 
modificaciones.  El metabolismo es más rápido en el ratón que en la 
rata, lo que origina un perfil metabólico semejante con una 
proporción relativamente mayor de derivados del glutatión por 
conjugación.  Se ha demostrado que el citocromo P-450 de microsomas 
humanos también metaboliza el cloruro de vinilideno.  

    El metabolismo del cloruro de vinilideno en roedores lleva al 
agotamiento de las reservas de glutatión y a la inhibición de la 
actividad de la glutatión- S- transferasa.  

1.4.  Efectos en animales de experimentación y sistemas celulares 

1.4.1 Enlaces covalentes en tejidos 

    Los marcadores radiactivos derivados del [14C]-cloruro de 
vinilideno forman enlaces covalentes en el hígado, el riñón y el 
pulmón de los roedores, lo que va asociado a toxicidad en esos 
órganos.  El enlace covalente y la toxicidad se agravan con el 
agotamiento del glutatión y se producen en el hígado y el riñón a 
dosis inferiores en ratones que en ratas.  Se ha observado  in vitro 
que varios metabolitos del cloruro de vinilideno establecen enlaces 
covalentes con tioles.  

1.4.2 Toxicidad aguda 

    Aunque las estimaciones de la CL50 aguda para el cloruro de 
vinilideno varían considerablemente, esta variación no enmascara el 
hecho de que el ratón es mucho más sensible a la sustancia que la 
rata o el criceto.  Los valores estimados de la CL50 a las 4 h 
variaron desde aproximadamente 8000 hasta 128 000 mg/m3 (2000-32 
000 ppm) en ratas alimentadas, 460-820 mg/m3 (115-205 ppm) en 
ratones alimentados y 6640-11 780 mg/m3 (1660-2945 ppm) en cricetos 
alimentados.  Pueden existir imprecisiones en los cálculos de la 
CL50 debido a que la relación concentración-mortalidad no es de 
carácter lineal.  En todas las especies, los machos parecían tener 
valores de CL50 más bajos que las hembras, y el ayuno (que agota 
las reservas de glutatión) aumentó la toxicidad en las tres 
especies.  Tras la administración oral, los valores de la DL50 
fueron aproximadamente 1500 y 200 mg/kg en ratas y ratones 
alimentados, respectivamente.  La toxicidad aguda por inhalación en 
animales de laboratorio se manifestó en forma de irritación de las 

mucosas, depresión del sistema nervioso central y cardiotoxicidad 
progresiva (bradicardia sinusal y arritmias).  Se observaron 
lesiones en el hígado, el riñón y el pulmón.  En el ratón, que es 
más sensible que la rata a la toxicidad hepática y renal del 
cloruro de vinilideno, la exposición a dosis tan reducidas como 40 
mg de cloruro de vinilideno/m3 (10 ppm) durante 6 h indujo lesiones 
renales y aumento de la replicación del ADN.  Como en el caso de la 
inhalación, los principales órganos afectados por la ingestión de 
cloruro de vinilideno son el hígado, el riñón y el pulmón.  La 
cadena de procesos que llevan a la hepatotoxicidad parece comenzar 
por un cambio temprano en los canalículos biliares, que se ve 
seguido por síntomas de lesiones mitocondriales.  A continuación se 
producen lesiones en el retículo endoplasmático y la muerte 
celular.  La toxicidad hepática y renal inducida por el cloruro de 
vinilideno no parece estar causada por peroxidación lipídica.  El 
aumento de las concentraciones intracelulares de Ca++ puede ser en 
parte responsable de la toxicidad para el hepatocito.  

    Los efectos tóxicos del cloruro de vinilideno dependen, al 
menos parcialmente, de la actividad del citocromo P-450 (que 
también puede participar en la detoxificación) y pueden agravarse 
por el agotamiento de las reservas de glutatión.  La hepatotoxicidad 
puede ser intensificada por el etanol y la tiroxina, inhibida por 
el ditiocarbo y la (+)-catequina y modulada por la acetona.  

1.4.3 Estudios a corto plazo 

    En estudios a corto plazo se han observado lesiones hepáticas, 
renales y, en menor grado, pulmonares en roedores expuestos por 
inhalación al cloruro de vinilideno a una concentración de 40-800 
mg/m3 durante 4-8 h/día, 4 o más días/semana.  El ratón demostró ser 
más sensible que la rata, el cobayo, el conejo, el perro y el mono 
ardilla, y la toxicidad fue distinta de unas familias de ratones a 
otras.  En general, las hembras eran menos sensibles que los machos.  
Se ha comunicado la aparición de hepatotoxicidad en la rata y el 
ratón expuestos intermitentemente a concentraciones de cloruro de 
vinilideno >800 mg/m3 (>200 ppm) y 220 mg/m3 (55 ppm), 
respectivamente.  Los niveles necesarios para producir 
hepatotoxicidad por exposición continua durante varios días fueron 
240 mg/m3 (60 ppm) para la rata y 60 mg/m3 (15 ppm) para el ratón.  
Estos tratamientos intermitentes y continuos también provocaron 
nefrotoxicidad en el ratón.  El ratón suizo macho resultó ser 
especialmente propenso a la toxicidad renal inducida por cloruro de 
vinilideno.  El ratón macho no sobrevivió a una exposición continua 
a corto plazo a 200 mg de cloruro de vinilideno/m3 (50 ppm).  El 
nivel aparente de no observación de efectos de hepatotoxicidad en 
el perro, el mono ardilla y la rata fue de aproximadamente 80 mg/m3 
(20 ppm) administrados en exposición continua durante 90 días.  En 
estudios de dosificación oral a corto plazo (aproximadamente 3 
meses) en la rata (hasta 20 mg/kg diarios) y el perro (hasta 25 
mg/kg diarios) no se observó prueba alguna de toxicidad aparte de 
una mínima lesión hepática reversible en la rata.  

1.4.4 Estudios a largo plazo 

    Los estudios a largo plazo de exposición intermitente al 
cloruro de vinilideno por inhalación revelaron que 300 mg/m3 (75 
ppm) sólo causaban ligeras lesiones hepáticas reversibles en la 
rata.  A 600 mg/m3 (150 ppm), la dosis más alta de exposición a 
largo plazo que puede tolerar la rata, se apreció lesión hepática 
con necrosis.  En el ratón se observó una elevada tasa de mortalidad 
con signos de lesión hepática a 200 mg/m3 (50 ppm).  Se observó 
toxicidad para el riñón en el tratamiento a largo plazo de ratones 
con 100 mg/m3 (25 ppm).  La administración de hasta 30 mg/kg al día 
de cloruro de vinilideno a la rata durante un año volvió a producir 
cambios hepáticos mínimos.  A partir de estos datos no se puede 
determinar claramente el nivel de no observación de efectos.  En 
otro estudio se observaron ciertas pruebas de que podía inducirse 
inflamación renal y necrosis hepática en la rata y el ratón, 
respectivamente, tras la administración oral a largo plazo de 
cloruro de vinilideno a dosis diarias de 5 mg/kg y 2 mg/kg, 

1.4.5 Genotoxicidad y carcinogenicidad 

    Se observó que el cloruro de vinilideno es mutagénico para 
bacterias y levaduras sólo en presencia de un sistema de activación 
metabólica de microsomas de mamíferos (S9).  El compuesto indujo 
síntesis no programada de ADN en hepatocitos aislados de rata y 
aumentó la frecuencia de intercambio de cromátidas hermanas y de 
aberraciones cromosómicas en cultivos celulares con S9.  En cambio, 
no se observó aumento en la mutación de genes de mamíferos.  Se ha 
comunicado un aumento pequeño pero estadísticamente significativo 
del enlace al ADN después de la exposición  in vivo.  El enlace al 
ADN fue más frecuente en células de ratón que de rata y mayor en el 
riñón que en el hígado tras exposiciones de 6 h a 40 y 200 mg de 
cloruro de vinilideno/m3 (10 y 50 ppm).  Además, el cloruro de 
vinilideno aumentaba ligeramente la síntesis no programada de ADN 
en el riñón de ratón.  No se observó prueba alguna de efectos 
letales dominantes o de efectos citogenéticos tras la exposición  in 
 vivo de roedores a excepción de un estudio que demuestra la 
inducción de aberraciones cromosómicas en la médula ósea del 
criceto chino.  

    Se han llevado a cabo estudios de carcinogenicidad en tres 
especies animales (rata, ratón y criceto).  En el ratón suizo macho, 
se vieron signos claros de carcinogenicidad (adenocarcinoma del 
riñón) tras una exposición intermitente a largo plazo a 100 ó 200 
mg de cloruro de vinilideno/m3 (25 ó 50 ppm) pero no a 0 ó 40 mg/m3 
(0 ó 10 ppm).  

    Los tumores de riñón pueden guardar alguna relación con la 
citotoxicidad renal observada y es posible que la lesión renal 
repetida lleve directamente a la respuesta carcinogénica por un 
mecanismo no genotóxico o bien que facilite la expresión del 
potencial genotóxico de los metabolitos en esta especie, sexo y 

órgano en concreto.  No obstante, esta conclusión es dudosa a la luz 
de los escasos datos disponibles sobre los efectos genéticos  in 
 vivo y el descubrimiento de que el cloruro de vinilideno podía 
haber actuado como iniciador.  

    En el mismo estudio, se observaron incidencias estadísticamente 
mayores de tumor del pulmón (principalmente adenomas en el ratón de 
ambos sexos) y carcinomas mamarios (en hembras), pero no se 
encontraron relaciones dosis-respuesta.  En rata adulta expuesta por 
inhalación, se comunicó un ligero aumento independiente de la dosis 
de tumores de la mama, así como un pequeño aumento de la leucemia 
cuando se exponía a la rata  in utero y recién nacida.  Estas 
observaciones no pudieron evaluarse.  

1.4.6 Efectos sobre la reproducción 

    No se encontró efecto alguno sobre la fecundidad de la rata 
continuamente expuesta al cloruro de vinilideno (hasta 200 
mg/litro, 200 ppm) en el agua de bebida.  La inhalación de hasta 
1200 mg de cloruro de vinilideno/m3 (300 ppm), durante 22-23 horas, 
por la rata y el ratón durante diversos periodos de la 
organogénesis no indujo anomalías fetales que no pudieran 
atribuirse a la toxicidad materna.  

    La inhalación de hasta 640 mg de cloruro de vinilideno/m3 (160 
ppm) durante 7 h/día en ratas y conejos o la ingestión de 
aproximadamente 40 mg/kg al día en la rata durante periodos 
críticos de la gestación no ejercieron efecto alguno sobre los 
embriones o los fetos en niveles inferiores al que produce la 
toxicidad materna, pero se observaron toxicidad embrionaria y fetal 
y anomalías fetales cuando se alcanzó el nivel que produce 
toxicidad en la madre, como lo demostró la menor velocidad de 
aumento de peso.  

1.5.  Efectos en el hombre 

    Una concentración de cloruro de vinilideno de 16 000 mg/m3 
(4000 ppm) provoca una intoxicación que puede llevar a la pérdida 
del conocimiento.  El cloruro de vinilideno estabilizado es también 
irritante para el tracto respiratorio, los ojos y la piel.  Se han 
comunicado lesiones renales y hepáticas correspondientes a 
exposiciones subanestésicas, prolongadas o repetidas a corto plazo.  
La evaluación de los estudios epidemiológicos se vio dificultada 
por el pequeño tamaño de las cohortes, la coexposición a cloruro de 
vinilo y la insuficiente atención al hábito de fumar.  Aunque no se 
encontró una incidencia mayor en grado estadísticamente 
significativo del cáncer en el hombre expuesto al cloruro de 
vinilideno, los estudios epidemiológicos fueron insuficientes y no 
se puede concluir que no entrañe un riesgo carcinogénico.  No se 
dispone de información sobre los efectos del cloruro de vinilideno 
en la reproducción humana.  

2.  Evaluación de los efectos en el medio ambiente y riesgos 
para la salud humana

2.1.  Evaluación de los efectos en el medio ambiente

    A consecuencia de la volatilización, la atmósfera constituye el 
principal compartimento ambiental del cloruro de vinilideno.  Puesto 
que la semivida de este compuesto en la troposfera es de unos dos 
días aproximadamente, parece poco probable que el cloruro de 
vinilideno contribuya a agotar la capa de ozono de la estratosfera.  
La lixiviación y la volatilización hacen que el suelo y los 
sedimentos sean compartimentos ambientales de menor importancia 
para el cloruro de vinilideno; el nivel de este hidrocarburo 
clorado en el medio acuoso se ve también reducido al mínimo por la 
rápida volatilización.  No se sabe si la degradación de compuestos 
como el tricloroetileno y el percloroetileno, que a menudo se 
encuentran en el agua, contribuye a aumentar apreciablemente los 
niveles de cloruro de vinilideno en el medio ambiente.  

    Las concentraciones de cloruro de vinilideno que se observan en 
las colecciones naturales de agua y los niveles de toxicidad aguda 
para peces y Daphnia indican que los riesgos de toxicidad aguda 
para el medio acuático son mínimos.  No se dispone de suficientes 
datos sobre toxicidad a largo plazo para evaluar los efectos 
subletales sobre los organismos acuáticos que viven en las 
proximidades de fuentes importantes de contaminación por cloruro de 
vinilideno, como aguas subterráneas contaminadas y puntos de 
vertido municipal e industrial.  

2.2.  Evaluación de los riesgos para la salud humana 

2.2.1 Niveles de exposición 

    La población general está expuesta a niveles muy bajos de 
cloruro de vinilideno.  El nivel máximo notificado en el agua de 
bebida es de 20 µg/litro, si bien se ha calculado que, en los 
Estados Unidos de América, la exposición individual diaria del 
ciudadano medio a través del agua de bebida es de <0,01 µg.  Los 
niveles de cloruro de vinilideno en los alimentos no suelen ser 
detectables; no se han notificado niveles superiores a 10 µg/kg.  
Los niveles en alimentos derivados de organismos acuáticos se 
desconocen, pero es probable que sean insignificantes (sección 
10.1).  Se han comunicado niveles de cloruro de vinilideno en el 
aire de hasta 52 µg/m3 (en el perímetro de una zona industrial).  En 
los Estados Unidos se han comunicado valores medios de 
concentración en el aire urbano de 20 ng/m3 en zonas no 
industriales y 8,7 µg/m3 en zonas industriales.  

    La exposición profesional tiene lugar especialmente en los 
procesos de producción y polimerización.  La respiración es la vía 
principal de entrada en el organismo y los límites de exposición 
máximos recomendados o promedios regulados a lo largo de un día de 
trabajo varían entre 8 y 500 mg/m3 (o la concentración más baja 
detectable con un margen de confianza), según el país.  Los límites 
de exposición a corto plazo varían entre 16 y 80 mg/m3 y los 

valores máximos entre 50 y 700 mg/m3.  Se ha encontrado que los 
niveles de cloruro de vinilideno en las atmósferas cerradas a las 
que algunos trabajadores se ven expuestos no superan los 8 mg/m3.  

2.2.2 Efectos agudos 

    En el ser humano, es probable que la inhalación de 
concentraciones elevadas de cloruro de vinilideno (muy 
aproximadamente iguales o superiores al umbral olfativo máximo de 
4000 mg/m3) provoque depresión del sistema nervioso central y pueda 
llevar al coma.  Basándose en la toxicidad aguda para animales, el 
cloruro de vinilideno puede ejercer efectos tóxicos en el hígado, 
el riñón o el pulmón a concentraciones muy inferiores al umbral 
olfativo mínimo de aproximadamente 2000 mg/m3.  La exposición al 
cloruro de vinilideno puede producir irritación en los ojos, el 
tracto respiratorio superior (a 100 mg/m3 en el hombre, Rylova 
1953) y la piel, lo cual se ha atribuido en parte a un agente 
estabilizante, el  p- metoxifenol.  

    En el ratón, más sensible que la rata a los efectos 
hapatotóxicos y nefrotóxicos del cloruro de vinilideno, se 
indujeron lesiones renales por exposición a cantidades tan 
reducidas como 40 mg de cloruro de vinilideno/m3 (10 ppm) durante 6 
h.  También se observaron hepatotoxicidad y nefrotoxicidad notables 
en la rata.  Tras el ayuno, que aumenta la toxicidad, la exposición 
de la rata a concentraciones de cloruro de vinilideno de 600 mg/m3 
(150 ppm) y 800 mg/m3 (200 ppm) durante 6 h provocó toxicidad en el 
hígado y el riñón, respectivamente.  Los estudios realizados en la 
rata indican que la ingestión de alcohol antes de la exposición 
puede acelerar el metabolismo y exacerbar la toxicidad del cloruro 
de vinilideno.  La toxicidad aguda depende de la especie, el sexo, 
la estirpe y el régimen de alimentación de los animales.  La 
distinta sensibilidad del ratón y la rata guarda relación con la 
diferente actividad del metabolismo oxidativo del cloruro de 
vinilideno en una y otra especie.  Aunque no se puede predecir si la 
rata o el ratón constituyen el modelo más adecuado para el ser 
humano, la actividad del metabolismo microsómico hepático del 
hombre es cuantitativamente semejante al de la rata, cuya 
susceptibilidad es relativamente baja.  No hay pruebas de que 
existan diferencias cualitativas en el metabolismo oxidativo del 
cloruro de vinilideno en el ser humano y el roedor.  

    Está claro que el margen entre las concentraciones capaces de 
producir toxicidad en animales (40 mg/m3 en el ratón) y los límites 
de exposición profesional establecidos por algunos países es 
insuficiente o inexistente.  

2.2.3 Efectos a largo plazo y genotoxicidad 

    La exposición prolongada o repetida a corto plazo a dosis 
subanestésicas puede producir lesiones renales y hepáticas.  
Basándose en estudios a largo plazo realizados en animales, en 
condiciones que simulaban la exposición profesional, se comunicó la 
aparición de cambios hepáticos a un nivel de exposición de 300 
mg/m3 (75 ppm) en la rata.  En el ratón, se observaron lesiones en 

el riñón y el hígado con 100 mg/m3 (25 ppm) y 200 mg/m3 (50 ppm), 
respectivamente.  Los datos sobre sensibilidad a los efectos tóxicos 
varían considerablemente de unos estudios a otros.  

    En los animales, el cloruro de vinilideno no parece influir en 
la capacidad reproductiva ni constituir un riesgo embriotóxico o 
teratogénico a dosis inferiores a las que producen toxicidad 
materna, pero este extremo no se ha estudiado en el hombre.  Cuando 
se utilizaron concentraciones capaces de producir toxicidad materna 
se observaron toxicidad embrionaria y fetal y anomalías fetales, 
reflejadas en la menor velocidad de aumento de peso.  

    El cloruro de vinilideno tiene efecto mutagénico en las 
bacterias y las levaduras siempre que actúe en presencia de un 
sistema metabólico de mamíferos.  También algunas células de 
mamíferos pueden sufrir lesiones del ADN y efectos mutagénicos  in 
 vitro .  En la mayoría de los estudios realizados en roedores  in 
 vivo no se observaron efectos genotóxicos medidos por la letalidad 
dominante ni desde el punto de vista citogenético, pero se ha 
comunicado la observación de aberraciones en células de la médula 
ósea del hámster chino.  El enlace al ADN y la reparación de éste  in 
 vivo en roedores fueron detectables pero mínimos.  Así pues, los 
estudios genéticos  in vivo sugieren algunos signos de toxicidad 
genética, pero, en la mayoría de los casos, los efectos fueron 
mínimos o negativos.  

    Se han llevado a cabo varios ensayos de carcinogenicidad en 
tres especies de animales de experimentación (ratones, ratas y 
hámsters) utilizando diversas vías de administración.  
Lamentablemente, la mayoría de estos estudios adolecían de graves 
limitaciones de diseño o de método para la evaluación de la 
carcinogenicidad.  Por vía oral no se observaron efectos 
carcinogénicos significativos en la rata.  En la rata adulta 
expuesta por inhalación, se notificó un aumento de los tumores de 
la mama que no guardaba relación con la dosis.  Se observó un ligero 
aumento de la leucemia en las ratas expuestas tanto  in utero como 
recién nacidas.  Estas observaciones no pudieron evaluarse.  En un 
estudio realizado en el ratón, se observó una mayor incidencia de 
adenocarcinomas de riñón en los machos con niveles de exposición de 
200 y 100 mg/m3 (50 y 25 ppm) pero no con 40 y 0 mg/m3 (10 y 0 
ppm).  En el mismo estudio, se observaron incidencias 
estadísticamente mayores de tumores del pulmón (principalmente 
adenomas en ambos sexos) y carcinomas mamarios (en hembras), pero 
no se descubrieron relaciones entre la dosis y la respuesta.  

    Los tumores del riñón pueden estar relacionados de algún modo 
con la citotoxicidad renal observada; puede ser que las lesiones 
repetidas del riñón lleven directamente a la respuesta 
carcinogénica por medio de un mecanismo no genotóxico o bien que 
faciliten la expresión del potencial genotóxico de los metabolitos 
en esta especie, este sexo y este órgano en particular.  No 
obstante, esta conclusión es dudosa en la ausencia de datos de 
dosis-respuesta suficientes sobre los efectos genéticos  in vivo, 
así como ante el descubrimiento de que el cloruro de vinilideno 
puede haber actuado como iniciador en un ensayo cutáneo en dos 
etapas en el ratón.  

    Los estudios epidemiológicos, aunque no dan pruebas 
estadísticamente significativas de que la exposición profesional al 
cloruro de vinilideno entrañe un riesgo mayor de cáncer no son 
adecuados para evaluar debidamente el riesgo carcinogénico del 
cloruro de vinilideno para el ser humano.  

    Aunque en las evaluaciones de algunos autores el exceso de 
defunciones por cáncer se atribuye al azar (a causa del reducido 
número de sujetos y del tamaño de las cohortes), el hecho de que 
aparezcan repetidamente valores más altos de lo esperado es digno 
de mención.  En los dos estudios de cohortes comunicados, se observó 
cáncer del pulmón en 7 casos, cuando cabía esperar 3,16 
defunciones.  El resultado no puede desecharse, aunque hay que tener 
presente la coexistencia de la exposición al cloruro de vinilideno 
(en uno de los estudios).  Puesto que las cohortes se determinaron 
según su exposición al cloruro de vinilideno, puede ser imposible 
excluir otras exposiciones que induzcan a error.  Las conclusiones 
comunicadas en materia de morbilidad (incluido un caso de carcinoma 
testicular) pueden ser útiles a título informativo.  La 
interpretación por parte de los autores de que la mayor morbilidad 
hepática guardaba relación con el consumo de alcohol por los 
sujetos no es válida, puesto que no se evaluó la ingestión de 
alcohol por todos los sujetos del estudio (y no sólo por los casos 

3.  Recomendaciones 

3.1 Recomendaciones para trabajos futuros 

    Es preciso disponer de mejores estimaciones de la producción 
mundial anual de cloruro de vinilideno y de las cantidades de 
cloruro de vinilideno que ingresan en el medio ambiente de todas 
las procedencias, ya sea en forma de cloruro de vinilideno como tal 
o por la degradación de otros productos químicos.  

    El destino ambiental previsto se basa en escasas pruebas 
experimentales.  Se necesita más información sobre las tasas de 
degradación y sobre los productos de transformación en el aire, el 
suelo, el agua y los sedimentos, y el metabolismo en especies no 
mamíferas representativas.  

    Deben llevarse a cabo estudios de toxicidad a largo plazo en 
los que se investiguen los diversos punto finales patológicos en 
especies acuáticas representativas (peces, crustáceos y moluscos).  
Deben definirse con más precisión los umbrales y los mecanismos de 
los efectos tóxicos que tiene la exposición al cloruro de 
vinilideno a corto y a largo plazo en el animal y el ser humano, 
como base para establecer niveles seguros de exposición.  

    Conviene hacer un uso más exhaustivo de los datos existentes en 
materia de carcinogenicidad.  Los nuevos estudios sobre 
carcinogenicidad deben hacerse según un protocolo aceptado de 
bioensayo durante un lapso de vida entera que tenga en cuenta 
específicamente las propiedades particulares del cloruro de 
vinilideno.  Esos estudios deben tener presentes la brevedad de la 

semivida de la sustancia en el organismo, la importancia de la edad 
al comienzo de la exposición, la duración de la exposición diaria y 
otros datos pertinentes que puedan estar relacionados con el 
establecimiento del régimen de dosificación.  Hay que seleccionar 
cuidadosamente las especies y estirpes de los animales de 
experimentación.  Los datos de toxicidad así como los datos 
metabólicos y farmacocinéticos correspondientes a estos animales 
también serían sumamente útiles.  

    Deben llevarse a cabo estudios de seguimiento a largo plazo 
sobre la morbilidad y la mortalidad en poblaciones enteras y no 
seleccionadas expuestas al cloruro de vinilideno.  

    Se necesitan estudios epidemiológicos que permitan evaluar los 
efectos de la exposición al cloruro de vinilideno (incluida la 
exposición prolongada a niveles reducidos) en poblaciones humanas.  
Es particularmente necesario disponer de información sobre efectos 
como la aparición precoz de enfermedades cerebrovasculares y 
cáncer; los estudios deben tener en cuenta los factores que 
introducen errores, como el hábito de fumar y el consumo de alcohol 
(posiblemente en un sistema de referencia de casos).  

    Debe recurrise a datos históricos como base de comparación con 
los resultados de las investigaciones en curso para poder evaluar 
los efectos protectores que han tenido las medidas de reglamentación 
durante los últimos años.  

    Para las investigaciones tanto en curso como futuras, un medio 
valioso de salvar el problema del reducido número de sujetos que 
hay en cada lugar de producción por separado sería aunar todos los 
datos de éstos y realizar estudios multicéntricos.  Debe 
investigarse en animales de experimentación el valor de la 
utilización de un agente con grupo sulfhidrilo como la 
 N- acetilcisteína en el tratamiento de la intoxicación por cloruro 
de vinilideno.  

    Es necesario comparar la farmacocinética y el metabolismo  in 
 vivo/in vitro del cloruro de vinilideno, especialmente en el 
riñón, el hígado y el pulmón, en animales de experimentación de 
distintas especies y en el ser humano, con el fin de comprender 
mejor los resultados obtenidos en estudios de toxicidad  in vivo .  Se 
precisan datos paralelos sobre la genotoxicidad potencial del 
cloruro de vinilideno en el lugar escogido para estudiar la 
carcinogénesis en distintas especies a fin de examinar el posible 
papel de un mecanismo genético.  

    A la luz de las conclusiones neurotoxicológicas comunicadas en 
el presente análisis, es necesario investigar el papel de los 
sistemas moduladores en la patogénesis de la intoxicación por 
cloruro de vinilideno.  

3.2 Protección personal y tratamiento de la intoxicación 

3.2.1 Protección personal 

    En los lugares de trabajo en la industria donde pueden 
producirse exposiciones a corto plazo por inhalación superiores a 
los límites recomendados, deben utilizarse mascarillas faciales 
completas con filtro para los vapores orgánicos y, en previsión de 
una emergencia, deben proporcionarse mascarillas con sistema de 
abastecimiento de aire.  Para evitar el contacto con el cuerpo, los 
operarios que manejen cloruro de vinilideno deben llevar ropa 
protectora, en buen estado, que incluya gafas de seguridad.  Debe 
mantenerse una ventilación constante dentro de las plantas 
industriales mediante respiraderos con filtros en los lugares donde 
puedan producirse derrames o fugas.  Se recomienda vigilar las 
emisiones de cloruro de vinilideno durante las operaciones de 
distribución.  En caso de una fuga, debe forzarse la evaporación del 
cloruro de vinilideno ya sea directamente si se trata de una 
cantidad pequeña o por evaporación controlada utilizando una espuma 
sintética de expansión.  Para disperar los vapores de la espuma 
pueden utilizarse aspersores de agua en cortinas.  

3.2.2 Tratamiento de la intoxicación en el hombre 

    En casos de exposición excesiva o de ingestión, debe 
consultarse a un médico.  Dadas las propiedades irritantes del 
cloruro de vinilideno, debe prestarse especial atención a los 
pulmones, la piel y los ojos.  Deben vigilarse las funciones del 
corazón, el hígado, el riñón y el sistema nervioso central.  Puesto 
que los datos correspondientes a animales indican que el cloruro de 
vinilideno produce un aumento notable de la sensibilidad a las 
arritmias cardiacas inducidas por la adrenalina, debe evitarse el 
empleo de este fármaco.  La hipotensión grave puede tratarse por 
transfusión, con sangre entera o sustitutos del plasma.  No se 
conoce antídoto alguno.  

    Un paciente intoxicado por inhalación de cloruro de vinilideno 
debe mantenerse abrigado en posición semiprona y en una atmósfera 
bien ventilada y fresca.  Las vías respiratorias deben mantenerse 
despejadas y debe administrarse oxígeno si el sujeto se encuentra 
en estado de estupor o de coma.  En caso necesario debe aplicarse 
respiración artificial.  

    Tras la ingestión de cloruro de vinilideno debe enjuagarse la 
boca con agua.  No debe provocarse el vómito por el riesgo de 
aspiración de cloruro de vinilideno hacia la laringe y los 
pulmones.  El lavado gástrico y/o la administración oral de carbono 
activado o de parafina líquida pueden ayudar a reducir la 
biodisponibilidad de cloruro de vinilideno si se administran dentro 
de la hora que sigue a la ingestión, pero pueden beneficiar al 
paciente hasta 4 horas después de la ingestión.  

    Los ojos expuestos a cloruro de vinilideno deben irrigarse 
inmediatamente con agua durante más de l5 minutos y debe acudirse 
al médico.  

    En caso de exposición cutánea, las ropas contaminadas deben 
retirarse y debe lavarse la zona afectada con agua y jabón.  

    See Also:
       Toxicological Abbreviations
       Vinylidene chloride (HSG 36, 1989)
       Vinylidene chloride (ICSC)
       Vinylidene Chloride  (IARC Summary & Evaluation, Volume 71, 1999)