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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY



    ENVIRONMENTAL HEALTH CRITERIA 68




    HYDRAZINE









    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 Orgnization
    Geneva, 1987


         The International Programme on Chemical Safety (IPCS) is a
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        ISBN 92 4 154268 3 

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CONTENTS


ENVIRONMENTAL HEALTH CRITERIA FOR HYDRAZINE

 1. SUMMARY

 2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

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

 3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    3.1. Natural occurrence
    3.2. Man-made sources
         3.2.1. Industrial production
         3.2.2. Methods of transport
         3.2.3. Disposal of waste
    3.3. Use pattern

 4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

    4.1. Transport and distribution between media
    4.2. Abiotic degradation
    4.3. Biodegradation
    4.4. Interactions with soil

 5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    5.1. Environmental levels
    5.2. General population exposure
    5.3. Occupational exposure
    5.4. Populations at special risk

 6. KINETICS AND METABOLISM

    6.1. Absorption and distribution
    6.2. Metabolism and excretion
    6.3. Reaction with body components

 7. EFFECTS ON ORGANISMS IN THE ENVIRONMENT

    7.1. Aquatic organisms
    7.2. Microorganisms
    7.3. Plants

 8. EFFECTS ON EXPERIMENTAL ANIMALS

    8.1. Single exposures
    8.2. Short-term exposures
         8.2.1. Inhalation exposure
         8.2.2. Other routes of exposure

    8.3. Biochemical effects and mechanisms of toxicity
         8.3.1. Effects on lipid metabolism
         8.3.2. Effects on carbohydrate and protein metabolism
         8.3.3. Effects on mitochondrial oxidation
         8.3.4. Effects on microsomal oxidation
         8.3.5. Effects on the central nervous system
    8.4. Reproduction, embryotoxIcity, and teratogenicity
    8.5. Mutagenicity and related end-points
         8.5.1. DNA damage
         8.5.2. Mutation and chromosomal effects
         8.5.3. Cell transformation
    8.6. Carcinogenicity
         8.6.1. Inhalation exposure
         8.6.2. Oral exposure

 9. EFFECTS ON MAN

    9.1. Poisoning incidents
    9.2. Occupational exposure
         9.2.1. Inhalation exposure
         9.2.2. Skin and eye irritation; sensitization
         9.2.3. Mortality studies

10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT

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

11. RECOMMENDATIONS FOR FURTHER STUDIES

12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

REFERENCES

WHO TASK GROUP ON HYDRAZINE

 Members

Dr B. Gilbert, CODETEC, University City, Campinas, Brazil

Professor P. Grasso, Robens Institute, University of Surrey,
   Guildford, Surrey, United Kingdom

Mr M. Greenberg, Environmental and Criteria Assessment Office,
   US  Environmental Protection Agency MD-52, Research Triangle
   Park, North Carolina, USA

Professor M. Ikeda, Department of Environmental Health, Tohoku
   University School of Medicine, Sendai, Japan  (Chairman)

Dr N.N. Litvinov, A.N. Sysin Institute of General and Community
   Hygiene,  USSR  Academy  of Medical  Science,  Moscow,  USSR
    (Vice-Chairman)

Dr G.B. Maru, Carcinogenesis Division, Cancer Research Insti-
   tute, Tata Memorial Center, Parel, Bombay, India

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

Dr E. Rauckman, Carcinogenesis and Toxicological Evaluation
   Branch, National Institute of Environmental Health Sciences,
   National  Toxicology Program, Research Triangle  Park, North
   Carolina, USA

Professor D.J. Reed, Environmental Health Sciences Center,
   Oregon State University, Corvallis, Oregon, USA

Dr E. Rosskamp, Institute for Water, Soil and Air Hygiene of
   the Federal Ministry of Health, Berlin (West)

Dr S. Susten, Document Development Branch, Division of Stan-
   dards   Development   and   Technology  Transfer,   National
   Institute  for  Occupational Safety  and Health, Cincinnati,
   Ohio, USA  (Rapporteur)

Professor J.A. Timbrell, University of London, School of
   Pharmacy, Toxicology Unit, London, United Kingdom

 Observers

Dr P. Schmidt (European Chemical Industry Ecology and Toxico-
   logy   Centre),  Bayer  AG,   Leverkusen-Bayerwerk,  Federal
   Republic of Germany

Dr D. Steinhoff (European Chemical Industry Ecology and Toxico-
   logy Centre), Bayer AG, Institute for Toxicology, Wuppertal,
   Federal Republic of Germany

 Secretariat

Professor F. Valic, Andrija Stampar School of Public Health,
   University of Zagreb, Zagreb, Yugoslavia  (Secretary) a

Dr T. Ng, Office of Occupational Health, World Health Organ-
   ization, Geneva, Switzerland

Ms F. Ouane, International Register of Potentially Toxic
   Chemicals,  United  Nations  Environment Programme,  Geneva,
   Switzerland

Dr T. Vermeire, National Institute of Public Health and
   Environmental  Hygiene,  Bilthoven,  Netherlands   (Temporary
    Adviser)

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



------------------------
a  IPCS Consultant.

NOTE TO READERS OF THE CRITERIA DOCUMENTS


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



                          *    *    *



    A  detailed data profile  and a legal  file can be  obtained
from  the International Register of Potentially Toxic Chemicals,
Palais des Nations, 1211 Geneva 10, Switzerland  (Telephone  no.
988400 - 985850).

ENVIRONMENTAL HEALTH CRITERIA FOR HYDRAZINE


    A  WHO  Task  Group  on  Environmental  Health  Criteria for
Hydrazine   met   in  Geneva   from  25  to   30  August,  1986.
Professor F. Valic 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 hydrazine.

    The draft of this document were prepared  by  DR T. VERMEIRE
of  the National Institute  of Public Health  and  Environmental
Hygiene, Bilthoven, the Netherlands.

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


                             * * *


    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.   The
United   Kingdom  Department  of  Health   and  Social  Security
generously supported the costs of printing.

1.  SUMMARY

    Anhydrous hydrazine is a caustic, fuming, hygroscopic liquid
at  ordinary  temperature  and pressure.   The  odour perception
threshold  is  3 -  9 mg/m3.  It  decomposes on heating  or when
exposed  to ultraviolet radiation to form ammonia, hydrogen, and
nitrogen.   This  reaction  may be  explosive,  especially  when
catalysed  by  certain  metals and  metal  oxides.   Spontaneous
ignition  can occur in contact with porous materials.  Hydrazine
hydrate, the principal compound produced, contains 64% by weight
hydrazine.  Hydrazine is basic and is a strong reducing agent.

    In  1981,  the world  production  capacity of  hydrazine was
estimated to be in excess of 35 000 tonnes.

    Sensitive  analytical  methods  have been  developed for the
determination  of hydrazine in  air, water, biota,  food, drugs,
and  cigarette  smoke.   Minimum detection  limits  reported are
2 µg/m3    air (gas chromatography), 5 µg/litre   water (colori-
metry), 1  µg/litre   blood,  plasma, or  urine  (gas  chromato-
graphy/mass  spectrometry), and 3000 µg/kg  drug  (gas chromato-
graphy).

    Hydrazine is not known to occur naturally, except perhaps in
the  tobacco plant.  Currently,  the primary uses  of  hydrazine
hydrate are as a raw material in the manufacture of agricultural
chemicals,  blowing agents, polymerization catalysts, and pharm-
aceutical  products,  and as  a  corrosion inhibitor  in  boiler
water.   Both the hydrate  and anhydrous hydrazine  are used  as
propellant fuels.

    Emission  factors for loss of hydrazine into the atmosphere,
estimated  for  the Federal  Republic  of Germany,  amounted  to
0.06  - 0.08  kg/tonne of  hydrazine produced  and 0.02  -  0.03
kg/tonne  of hydrazine during  handling and further  processing.
Accidental  discharges into air, water, and soil can result from
bulk storage, handling, transport, and improper waste disposal.

    At  production facilities, data show  that concentrations of
up  to 0.35 mg/m3 and, occasionally, up to 1.18 mg/m3, can occur
during  production under normal conditions.   During handling of
the  fuel, concentrations of up to 0.25 mg/m3 have been measured
under  normal conditions, exceptionally rising to 2.59 mg/m3.  A
level  of  800 mg/m3 was  measured at the  site of a  leak in an
industrial  plant.   The general  population  may be  exposed to
hydrazine  vapour  via  accidental  discharge.   Evaporation  of
hydrazine from a liquid spill can be sufficient to  generate  an
atmospheric concentration as high as 4 mg/m3, 2 km  downwind  of
the spill.

    Hydrazine  is degraded rapidly in air through reactions with
ozone,  hydroxyl  radicals,  and nitrogen  dioxide.  In polluted
air,  the life-time of hydrazine is estimated to be of the order
of  minutes.   In  a clean  atmosphere,  the  life-time will  be
approximately 1 h.  In soil, aqueous hydrazine is  adsorbed  and
decomposed  on clay surfaces under aerobic conditions.  The rate

of  degradation of  hydrazine in  water is  highly dependent  on
factors  such  as  pH, temperature,  oxygen content, alkalinity,
hardness, and the presence of organic material and  metal  ions.
The  compound  is  biodegradable by  microorganisms in activated
sludge.  However, at concentrations above 1 mg/litre, it is also
toxic for these microorganisms.

    The blue algae Microcystis aeruginosa was the most sensitive
aquatic  species tested with  respect to hydrazine;  the  10-day
toxicity  threshold was reported  to be 0.00008  mg/litre.  Fish
species showed LC50 values of between 0.54 and 5.98 mg/litre.  A
test  to assess damage to  the embryo showed a  lowest-observed-
adverse-effect level of 0.1 mg/litre for the fathead minnow.  In
view of the low octanol/water partition coefficient of hydrazine
and its ready degradation, it will not bioaccumulate.  Hydrazine
is toxic for plants and can inhibit germination.

    Hydrazine  is absorbed rapidly through the skin or via other
routes of exposure. It is rapidly distributed to, and eliminated
from,  most  tissues.  In  mice and rats,  part of the  absorbed
hydrazine is excreted unchanged, and part as  labile  conjugates
or  as  acid-hydrolysable  derivatives  via  the  urine.    When
hydrazine  is metabolized, a  significant amount of  nitrogen is
produced, which is excreted via the lungs.

    In  human beings, hydrazine is irritating to the skin, eyes,
and  respiratory tract.  It is  a strong skin sensitizer.   In a
number of cases of accidental exposure, severe  adverse  effects
were observed, principally in the central nervous system, liver,
and kidneys.

    In experimental animals, in addition to the  above  effects,
common  observations following single  exposure include loss  of
body  weight, anaemia, hypoglycaemia, fatty  degeneration of the
liver,  and  convulsions.   Continuous exposure  of  mice, rats,
monkeys, and dogs to levels of 0.26 and 1.3 mg/m3 for  6  months
resulted in adverse effects in all species at 1.3 mg/m3  and  in
mice (fatty liver) and rats (decrease in growth), also  at  0.26
mg/m3.  When rats were treated with hydrazine in  the  drinking-
water  at  0.0003 -  0.3 mg/kg body  weight per day,  no adverse
effects were observed at levels of 0.003 mg/kg or less.  This is
the  only study in  which a no-observed-adverse-effect  level by
the oral route in rats has been reported.  No data are available
for  establishing  a  no-observed-adverse-effect  level  by  the
inhalation route.

    Data  are lacking concerning the effects of hydrazine on the
human embryo or fetus.  In studies on rats and  mice,  hydrazine
administered  by injection, orally,  or through inhalation  pro-
duced  adverse effects on embryos and fetuses, when administered
at  doses that were toxic  for the mother.  The  adverse effects
observed   in  these  studies  included  increased  resorptions,
reduced   fetal  weight,  increased  perinatal   mortality,  and
increased  incidences of litters and fetuses with abnormalities.
The  abnormalities  observed  were primarily  supernumerary  and
fused  ribs, delayed ossification, moderate  hydronephrosis, and

moderate  dilation of brain ventricle.  These abnormalities were
considered  to be minor by  the authors.  On the  basis of these
studies, it was concluded that, in the absence of human data, it
is prudent to assume that hydrazine would have an adverse effect
on  the  human embryo  or fetus at  levels near those  producing
toxic  effects in the  mothers.  Such exposures  may occur  from
accidental spillages.

    Hydrazine  caused increased DNA damage and repair in vitro.
No  increased unscheduled DNA synthesis was observed in the germ
cells  of mice after exposure  in vivo.  Hydrazine induced indir-
ect  methylation  of O6  and N7 of  guanine in the  liver DNA of
rodents  after  in vivo  exposure to toxic doses.  It also induced
gene mutations and chromosome aberrations in a variety  of  test
systems  including plants, phages, bacteria, fungi, Drosophila,
and  mammalian cells  in vitro .  However, in gene mutation assays
using  bacteria,  there  were variable  responses  following the
addition  of rat liver metabolic  activation systems.  Hydrazine
was found to transform hamster and human cells  in vitro .  It did
not  induce  chromosome  aberrations, micronuclei,  or  dominant
lethals   in  mice in  vivo, but  chromosomal  aberrations  were
reported in rats  in vivo .

    Hydrazine vapour induced nasal tumours, most of  which  were
benign, in Fischer 344 rats, following inhalation  exposure  for
12  months to concentrations of 1.3 or 6.5 mg/m3 with subsequent
observation for 18 months, and in Syrian golden hamsters exposed
to  6.5 mg/m3 with subsequent  observation for 12 months.   Such
effects  were not seen in C57BL/6 mice exposed to concentrations
of  0.06, 0.33, or 1.3 mg/m3 for 12 months followed by 15 months
of  observation,  except  for  an  increased  incidence  of lung
adenomas  of borderline significance  at 1.3 mg/m3.   In several
limited  gavage and drinking-water studies, hydrazine induced an
increased  incidence,  in  some cases  dose-related, of multiple
pulmonary  tumours in various mouse  strains and in Cb/Se  rats.
In  CBA/Cb/Se and BALB/c/CB/Se  mice, an increased  incidence of
hepatocarcinomas was also induced.  A very low,  but  increased,
incidence of hepatocarcinomas was observed in male  Cb/Se  rats.
No tumours were observed in hamsters.

    On  the basis of the carcinogenicity studies on experimental
animals,  there is evidence that hydrazine is an animal carcino-
gen.    Human  data  are  inadequate.    Hydrazine  induced  DNA
damage in   vitro, methylation  of  DNA  guanine in  vivo,   and
positive results in  in vitro  mutagenesis assays.

    Making an overall evaluation, hydrazine can be  regarded  as
posing  little  hazard  for  the  general  population  at normal
ambient levels.  However, in the work-place and under conditions
of  accidental  exposure,  hydrazine can  present  a significant
health hazard.  Human data are limited but show  that  hydrazine
may affect the central nervous system, liver, and  kidneys.   In
addition, it may produce skin and eye irritation and skin sensi-
tization.  The results of animal studies suggest that effects on
human  beings  may also  include  embryotoxicity at  levels near
those producing toxic effects in the mothers and adverse effects

on  the  respiratory system.   On the basis  of the evidence  of
carcinogenicity  in animals and  positive results in  short-term
tests,  it  would  be prudent  to  consider  hydrazine to  be  a
possible  human  carcinogen and,  therefore,  the levels  in the
environment should be kept as low as feasible.  It can  also  be
concluded  that hydrazine may present  a hazard for the  aquatic
environment and plant life.

    Further studies are needed on: (a) dose-response in relation
to DNA alkylation, damage to the nasal epithelium, and pulmonary
effects;  (b)  skin sensitization,  focusing on cross-reactivity
with  hydrazine  derivatives; (c)   dermal irritation-promotion;
(d) dose-response in sensitive fish species in relation to diet;
(e) metabolism with regard to effects on DNA; and (f) effects of
continuous  low-level  exposure  on  reproduction  in  sensitive
rodent species.

2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS 

2.1.  Identity

Chemical formula:             N2H4

Chemical structure:           H   H
                              |   |
                              N - N
                              |   |
                              H   H

Relative molecular mass:      32.05

Common name:                  hydrazine

Common synonyms:              diamide, diamine, anhydrous hydra-
                              zine, hydrazine base

Common trade names:           Aerozine-50 (a 1:1 w/w fuel mixture
(of mixtures)                 of anhydrous hydrazine and 1,1-
                              dimethylhydrazine); Hydrazine
                              hydrate (N2H4 H2O) (a 1:1 molar
                              mixture of anhydrous hydrazine and
                              water; Levoxin (a 15-64% aqueous
                              solution); SCAV-OX (a 35-64% aqueous
                              solution); Zerox (a 15-64% aqueous
                              solution)

CAS chemical name:            hydrazine

CAS registry number:          302-01-2

Conversion factors:           1 ppm = 1.31 mg/m3 at 25 °C and
                              101.3 kPa (760 mmHg)
                              1 mg/m3 = 0.76 ppm

    Hydrazine exposures are always expressed as exposure to free
base  N2H4.  The actual  compound used is  given in  parentheses
(sections, 6, 8, 9).

2.2.  Physical and Chemical Properties

    Anhydrous  hydrazine  is  a caustic,  fuming,  highly polar,
weakly  basic,  hygroscopic  liquid at  ordinary temperature and
pressure.   It is a combustible  substance, burning with a  blue
flame.   The pure compound decomposes on heating or when exposed
to ultraviolet radiation to form ammonia, hydrogen,  and  nitro-
gen.   This reaction may be explosive, especially when catalysed
by  certain metals and metal oxides.  Hydrazine can ignite spon-
taneously  in air, when  in contact with  porous materials.   In
aqueous  solution,  considerable  hydrogen bonding  takes place.
Hydrazine  and water form a  constant boiling mixture that  con-
tains  68% by weight of hydrazine and boils at 120.5 °C.  Hydra-
zine  and water also  form the compound  hydrazine  monohydrate,
which  contains 64% hydrazine by weight.  Hydrazine solutions in

water have basic properties.  Hydrazine is a  powerful  reducing
agent.   Autooxidation  occurs  in  alkaline  solutions  and  is
strongly  catalysed  by  metal ions,  notably  copper,  yielding
hydrogen  peroxide  as  a by-product.   Decomposition of aqueous
hydrazine  occurs in  the presence  of metal  catalysts such  as
platinum or Raney nickel.

    Some physical and chemical properties of hydrazine  and  its
hydrate are given in Table 1.

2.3.  Analytical Methods

    A selection of analytical methods for the  determination  of
hydrazine in air, water, biota, drugs, and smoke is presented in
Table 2.  A review of methods can be found in Schmidt (1984).

    Gas  chromatographic  methods  are the  most specific assays
available   providing  that  the  chromatographic  behaviour  of
hydrazine  is  improved  by  derivatization,  for  example,   by
reaction  with p-dimethylaminobenzaldehyde  or 2,4-pentanedione.
Hydrazine  can be determined simultaneously with its derivatives
using  these methods.  Colorimetric and  titrimetric methods are
subject  to  interference, especially  by hydrazine derivatives.
Direct-reading  papers  or  indicating  tubes,  based  on  these
colorimetric  methods, are available commercially  with reported
detection limits of 65 µg/m3  for tapes and 330 µg/m3  for tubes
(US NIOSH, 1978; Schmidt, 1984).

    The  instability  of  hydrazine  can  present  a  problem in
aqueous  samples.   Usually,  acidification of  the samples with
sulfuric acid will prevent degradation of hydrazine.

Table 1.  Some physical and chemical properties of hydrazine
and its hydrate
---------------------------------------------------------------------------
Property                  Anhydrous hydrazine     Hydrazine hydrate
                          (100% N2H4)             (64% N2H4)
---------------------------------------------------------------------------
Physical state            liquid                  liquid

Colour                    colourless              colourless

Odour                     ammoniacal and pungent  ammoniacal and pungent

Odour perception          3 - 9 mg/m3a            3 - 9 mg/m3

Melting point             2 °C                    -51.5 °C

Boiling point             113.5 °C                120.1 °C (azeotrope)

Flash point               38 °C (open cup)        75 °C (open cup)

Flammable limits          1.8 - 100%              3.4 - 100%

Vapour pressure           1.39 kPa (10.4 mmHg)    1 kPa (7.5 mmHg) at 20 °C
                          at 20 °C

Density                   1008 g/litre            1032 g/litre at 20 °C
                          at 20 °C

Relative vapour density   1.1

log n-octanol/water       -3.08
 partition coefficient

Solubility in water       infinite                infinite

Surface tension           66.7 dyne/cm at 25 °C   74.2 dyne/cm at 25 °C
-----------------------------------------------------------------------------
a  From: Jacobson et al. (1955, 1958).


Table 2.  Sampling, preparation, analysis
---------------------------------------------------------------------------------------------------------
Medium  Sampling method/      Analytical method         Detection   Comments                   Reference
        pretreatment                                    limit
---------------------------------------------------------------------------------------------------------
Air     trapping in dilute    colorimetry after reac-   20 µg/m3    sample size 100 litre;     US NIOSH 
        hydrochloric acid     tion with p-dimethyl-                 suitable for personal and  (1977a)
                              aminobenzaldehyde                     area monitoring; rec-
                                                                    ommended range is
                                                                    589 - 3440 µg/m3

Air     trapping on sulfuric  gas chromatography with   2 µg/m3     sample size 96 litre;      US NIOSH 
        acid-coated silica-   flame-ionization detec-               suitable for personal and  (1977b)
        gel; desorption       tion after derivatiza-                area monitoring; rec-
        with water            tion with 2-furaldehyde               ommended range is
                              and extraction into                   2 - 60 000 µg/m3
                              ethyl acetate

Air     trapping in chilled   gas chromatography of     5 µg/m3     sample size 2 litre;       Holtzclaw 
        acetone               acetone derivative with               suitable for area          et al.
                              a nitrogen detector                   monitoring                 (1984)

Water   sample must be acidi- colorimetry after re-     5 µg/       recommended range is       ASTM (1981); 
        fied when not anal-   action with p-dimethyl-   litre       5 - 150 µg/litre           Velte
        ysed immediately      aminobenzaldehyde                                                (1984)

Water                         polarography after re-    50 µg/                                 Slonim & 
                              action with 5-nitro-      litre                                  Gisclard
                              salicylaldehyde                                                  (1976)

Water   sample adjusted to    gas chromatography with   100 µg/     recommended range is       Dee (1971)
        pH 6 - 9              flame-ionization detec-   litre       100 - 50 000 µg/litre
                              tion after derivatiza-
                              tion with 2,4-pentane-
                              dione

Urine,  sample adjusted to    gas chromatography with   400 µg/     p-bromobenzaldehyde        Timbrell 
water   pH 3                  nitrogen detection after  litre       used as internal standard  et al.
                              derivatization with p-                                           (1977)
                              chlorobenzaldehyde and
                              extraction with methylene
                              chloride
---------------------------------------------------------------------------------------------------------

Table 2.  (contd.)
---------------------------------------------------------------------------------------------------------
Medium  Sampling method/      Analytical method         Detection   Comments                   Reference
        pretreatment                                    limit
---------------------------------------------------------------------------------------------------------

Blood   blood pretreated      colorimetry after re-     200 µg/     detectable range 200 -     Reynolds & 
        with trichloroacetic  action with p-dimethyl-   litre       2900 µg/litre; a serum     Thomas
        acid to precipitate   aminobenzaldehyde                     blank should be included   (1965); 
        protein                                                                                Springer
                                                                                               et al. 
Urine   urine adjusted to pH 3                                                                 (1981)

Blood                         fluorimetry after reac-   5 µg/                                  Lewalter 
                              tion with p-dimethyl-     litre                                  et al.
                              aminobenzaldehyde                                                (1984)

Drugs   sample dissolved      gas chromatography with   3000 µg/kg  the method was used in     Matsui et 
        in water and          nitrogen detection after  drug or     the analysis of isoniazid  al. (1983)
        centrifuged           derivatization with ben-  formul-     and hydralazine
                              zaldehyde and extraction  ation
                              into n-heptane

Cigar-  trapping in penta-    gas chromatography with   0.002 µg/   the method was also used   Liu et al.
ette    fluorobenzaldehyde    electron-capture detec-   20 cigar-   for the analysis of        (1974)
smoke   in methanol           tion after extraction     ettes       tobacco
                              with ether and enrich-
                              ment by thin-layer chroma-
                              tography with elution by
                              ether

Plasma,                       gas chromatography/mass   1 µg/       15 N -hydrazine used as     Timbrell 
biolo-                        spectrometry after deriv- litre       the internal standard      et al.
gical                         atization with pentafluoro-                                      (1982);  
media                         benzaldehyde, adsorption                                         Blair  
                              on silica, elution with                                          et al.
                              hexane                                                           (1985)
---------------------------------------------------------------------------------------------------------


3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

3.1.  Natural Occurrence

    The only natural occurrence of hydrazine reported was in the
tobacco  plant (Liu et  al., 1974).  Model  system studies  have
indicated  that  nitrogenase-bound  hydrazine may  be  an inter-
mediate in biological nitrogen fixation (Jackson et  al.,  1968;
Mitchell & Scarle, 1972; Thorneley et al., 1978).

3.2.  Man-Made Sources

    Hydrazine can be released into the atmosphere during venting
operations, storage, and transfer.  In the Federal  Republic  of
Germany,  the emission factor for the production of hydrazine is
estimated  to  be 0.06  - 0.08 kg/tonne.   It is estimated  that
0.02  - 0.03 kg of hydrazine is lost to the environment for each
tonne  of hydrazine subjected to handling and further processing
(Brugger, 1983).  Accidental discharge into water, air, and soil
can  result from bulk storage, handling, transport, and improper
waste disposal.

3.2.1.  Industrial productiona 

    Most production methods are based on the ketazine process, a
variation of the Raschig process, in which ammonia  is  oxidized
by  chlorine or chloramine in the presence of aliphatic ketones,
usually acetone.  The resulting ketazine is then  hydrolysed  to
hydrazine.   In a recent  method, hydrogen peroxide  is used  to
oxidize  ammonia in  the presence  of a  ketone.   A  production
process of minor importance involves the reaction  between  urea
and sodium hypochlorite (Schiessl, 1980; Schmidt, 1984).

    The  world  production capacity  was  estimated to  be about
36 000  tonnes  in 1981,  not  including countries  with planned
economies  (Schmidt, 1984).  In addition to hydrazine hydrate, a
small  amount  of anhydrous  hydrazine  is produced.   In  1964,
domestic  consumption in the  USA was approximately  7000 tonnes
(Raphaelian,  1966).  In 1974, the  total production in the  USA
was  reported to  be 17 000  tonnes (US  NIOSH,  1978;  Schmidt,
1984).   A more  recent estimate  for the  USA is  a  production
capacity  of  17 240  tonnes in  1979.   In  the same  year, the
production capacity was 6400 tonnes in the Federal  Republic  of
Germany, 3200 tonnes in France, 6500 tonnes in Japan,  and  1900
tonnes in the United Kingdom (Schiessl, 1980; Schmidt, 1984).

3.2.2.  Methods of transport

    In  1978, it was reported  that the US Department  of Energy
Management  annually  transported an  average  of 600  tonnes of
hydrazine fuel and 900 tonnes of hydrazine-1,1-dimethylhydrazine
fuel  (Aerozine-50) by rail, road,  and ship.  These fuels  were
transported  in  aluminium  tank  cars,  stainless  steel   tank
trailers, or in stainless steel drums (Watje, 1978).


    Current  international regulations require the  transport of
hydrazine  hydrate and its aqueous solutions in metal containers
with  polyethylene liners, in plastic canisters, or in stainless
steel containers.

3.2.3.  Disposal of waste

    Hydrazine  has been disposed  of by dilution  with water  to
form at least a 400 g/litre solution, followed by neutralization
with  dilute  sulfuric  acid and  drainage  into  a  sewer  with
abundant  water (IRPTC, 1985).  However, it should be noted that
even  very  dilute solutions  of 0.1 mg/litre  can be toxic  for
aquatic  life (section 7.1).  Alternatively,  hydrazine has been
burnt in an open pit after the addition of a hydrocarbon solvent
(IRPTC,  1985).  A better procedure  is to dilute with  abundant
water   and  then  oxidize   the  diluted  solution   (to  below
20 g/litre)  with  hydrogen  peroxide, calcium  hypochlorite, or
sodium hypochlorite before draining into a sewer (NEPSS, 1975).

    Hydrazine  vapour emissions can be  controlled by scrubbing,
using water as the scrubbing liquid, or by the direct  flame  of
catalytic incineraton (Gordon & Lewandowski, 1980).

    Hydrazine   sulfate,  a  commonly-used  derivative,  may  be
disposed of by incineration (IRPTC, 1985).

3.3.  Use Pattern

    The  first  important  use of  hydrazine  was  as  a  rocket
propellant.  In 1964, 73% of the hydrazine consumed was used for
this  purpose in the USA.   The remainder was mainly  used as an
intermediate  in the synthesis of agricultural chemicals such as
maleic hydrazine, blowing agents for plastics, drugs such as the
antitubercular  isoniazid and the  antihypertensive hydralazine,
and the solder fluxes, hydrazine bromide and hydrazine chloride.
Aqeous  hydrazine  was  in  use  at  that  time as  a  corrosion
inhibitor  in boiler water (Raphaelian, 1966).  This use pattern
has shifted towards a relatively greater use of hydrazine  as  a
chemical intermediate.  For the year 1977, it was estimated that
only 5% of the world production of hydrazine was used  as  fuel,
while  19% was  used for  boiler water  treatment, 32%  for  the
synthesis of agricultural chemicals, and 34% for  the  synthesis
of  blowing agents (Schiessl, 1980).  Currently, the main use of
hydrazine  hydrate as a  raw material is  in the manufacture  of
agricultural  chemicals (40%), blowing agents (33%), polymeriza-
tion catalysts, and pharmaceutical products.  Use as a corrosion
inhibitor in boiler water (15%)  continues, and there are appli-
cations as a chemical reducing agent in the metal-plating, metal

---------------------------------------
a All  production  capacities  and  consumption  figures  were
   calculated   for   anhydrous   hydrazine,  although   actual
   production  and consumption was  of hydrazine hydrate  or of
   more dilute aqueous mixtures.

recovery,  and  photographic industries,  and  as an  ignitor in
explosives (Schiessl, 1980; Schmidt, 1984).  Smaller amounts are
used  as a rocket propellant  and emergency fuel (Pitts  et al.,
1980;  Wald  et al.,  1984).  A very  small amount of  anhydrous
hydrazine  is used  as a  monopropellant in  space vehicles  and
satellites (Schmidt, 1984).

4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

4.1.  Transport and Distribution Between Media

    Pure  hydrazine has  a low  vapour pressure  and  is  highly
soluble  in water.  Nevertheless,  the evaporation rate  from  a
liquid  spill  can  be  sufficient  to  generate  an atmospheric
concentration  of  4 mg/m3,  2  km downwind  under  unfavourable
meterological  conditions.  Dilution with large amounts of water
reduces  the evaporation rate significantly (MacNaughton et al.,
1981).

4.2.  Abiotic Degradation

    Alkaline solutions of hydrazine in water can be  subject  to
autooxidation  by  dissolved  oxygen.  Hydrogen  peroxide  is an
important  intermediate  (Audrieth  &  Ogg,  1951).   In  acidic
solutions  or in the absence  of metal ions, notably  copper, no
appreciable  degradation was observed in aerated distilled water
(Gormley  & Ford, 1973;  MacNaughton et al.,  1981).  Gormely  &
Ford (1973)  measured a rapid oxygen depletion from 0.02 to 0.1%
alkaline solutions of hydrazine in the presence of  copper  ions
and  developed  a  mathematical expression  relating the aqueous
degradation  rate of hydrazine  to the concentrations  of hydra-
zine,  copper ions, and oxygen  at constant pH and  temperature.
Degradation  rates  for  dilute hydrazine  solutions were highly
variable  (Slonim & Gisclard,  1976; MacNaughton et  al., 1981).
Hydrazine was almost completely degraded within one day in muddy
river water, sampled directly after a rain storm.   However,  in
softened,  filtered water at the  same temperature and with  the
same  dissolved oxygen content, but  a lower initial pH,  little
degradation  occurred  within 4  days.   The main  factors  that
favour abiotic hydrazine degradation are the presence of certain
metal ions, organic material, in general, and organic oxidizers,
in  particular,  increased  hardness,  and  high  pH  (Slonim  &
Gisclard, 1976).

    In air, hydrazine can be oxidized in a number  of  different
ways.   There is no  information on how  hydrazine in the  atmo-
sphere is degraded.  The destruction of hydrazine by  ozone  and
by  hydroxyl radicals has been experimentally investigated (Hack
et  al., 1974; Harris  et al., 1979,  Pitts et al.,  1980).  The
rate of hydroxyl radical reaction with hydrazine was found to be
a linear function of the hydrazine concentration, independent of
temperature  and pressure.  Assuming an average hydroxyl radical
concentration of 106 radicals/cm3 for the lower troposphere, the
half-life of hydrazine with respect to this radical is estimated
to  be about 3  h (Harris et  al., 1979; Pitts  et  al.,  1980).
Assuming  an average level of 80 µg  ozone/m3 air (Singh et al.,
1978),  the lifetime of hydrazine with respect to ozone would be
approximately  1 h.  Nitrogen dioxide also reacts with hydrazine
(Pitts  et al., 1980; Tuazon et al., 1982).  In a polluted atmo-
sphere,  the lifetime would be of the order of minutes (Pitts et
al., 1980; Tuazon et al., 1982; Schmidt, 1984).  Diazene, hydro-
gen  peroxide, and small  amounts of nitrous  oxide and  ammonia
have been identified as products of these reactions  (Tuazon  et
al., 1982).

4.3.  Biodegradation

    Hydrazine  has  been shown  to  be co-metabolized  mainly to
nitrogen  gas  by the  nitrifying bacterium  Nitrosomonas  (Kane &
Williamson, 1983).  Preliminary studies have also indicated that
hydrazine can be reduced to ammonia by nitrogenase isolated from
the   nitrogen-fixing   bacterium  Azobacter  vinelandii  (Davis,
1980).   When hydrazine was  added continously to  a waste-water
treatment  plant, only concentrations  below 1 mg/litre  ensured
complete  absence  of the  compound  from the  effluent, without
inhibiting treatment efficiency (Farmwald & MacNaughton, 1981).

4.4.  Interactions with Soil

    Heck  et al. (1963) found that dilute hydrazine was adsorbed
in  a column  of soil  or decomposed,  if the  soil contained  a
moderate  amount  of  clay.   Probably,  decomposition  on  clay
particles  was more important  than adsorption.  Another  factor
influencing  adsorption  is  the  organic  content  of  the soil
(Isaacson  et al., 1984).   Dilute hydrazine leached  completely
through a column of sand (Heck et al., 1963).



5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

5.1.  Environmental Levels

    No  data on environmental levels of hydrazine are available.
This  is because degradation is so rapid that measureable levels
are not normally encountered (Schmidt, 1984).

5.2.  General Population Exposure

    Hydrazine  levels of  23 -  43 ng/cigarette  were  found  in
cigarette smoke by Liu et al. (1974).

    Traces of hydrazine have been found in samples of commercial
maleic  hydrazide, one of the uses of which is to inhibit sucker
growth on tobacco.  However, the amount of hydrazine measured in
tobacco  that had been  treated with maleic  hydrazide (12 -  51
ng/cigarette)  was not very much different from that measured in
untreated  tobacco  (14  - 22  ng/cigarette), indicating another
source of hydrazine in tobacco (Liu et al., 1974).

    It  has  been  reported that  analyses  of hydrazine-treated
boiler  water and the condensate of steam, which could have been
in  contact with food, confirmed  the presence of hydrazine  (US
FDA, 1979).

    District heating water has been mentioned as  an  additional
potential  route of accidental  human exposure.  This  water may
contain  a low concentration of  hydrazine as a corrosion  inhi-
bitor.  If this water is used to heat tap water and there  is  a
leak  inside the heat-exchanger at  the user end, the  tap water
may  be contaminated.   Cases have  been reported  in which  hot
water  became contaminated with levels  of up to 10.72  mg/litre
and drinking-water, up to 0.47 mg/litre (Bodenschatz, 1986).

5.3.  Occupational Exposure

    Workers  may be exposed to hydrazine at facilities producing
hydrazine  itself and those producing its salts and derivatives,
at  propulsion  testing  and  rocket  launching  sites,  and  at
locations  where aircraft using  hydrazine as an  emergency fuel
are  assembled  or  refueled.   Workers  at  plants  using high-
pressure  boilers are potentially  exposed to relatively  dilute
solutions  of hydrazine.  The  number of workers  and levels  of
exposure  for  sites  in the USA are given in Table 3 (US NIOSH,
1986).   Earlier and essentially similar data are reported by US
NIOSH (1978) and Suggs et al. (1980).

    Workers   normally  exposed  to  anhydrous  or  concentrated
hydrazine  are  provided  with respiratory  and skin protection.
The  difference between air levels outside and inside protective
masks  was illustrated by Cook et al. (1979) who found levels of
0.29  -  2.59 mg/m3  outside the masks  at a rocket  propellant-
handling facility, and levels below the detection limit of 0.013
mg/m3 inside the masks.

    Much  higher levels (800 mg/m3) were observed at the site of
a leak (Suggs et al., 1980).

Table 3.  Occupational exposure to hydrazine in the USA
---------------------------------------------------------------------
Site                  Approximate numbers     Measured levels (mg/m3)
                            exposed           Normal     Exceptional
                      Normal    Potential
---------------------------------------------------------------------
A   Rocket testing    10        100           0.01-0.02  0.14a
B   Production        100       800           < 0.13    0.13-0.26b
C   F-16 fighter      32                      -          0.04-0.05
     station
D   Rocket testing    10        300           no data    no data
E   F-16 assembly     51        16 500        0.04-0.25  no data
F   Space-craft       no data   14 000        no data    no data
     launching
G   Derivative manu-  < 25     no data       < 0.13    ca. 0.13
     facturer
H   Production        no data   1100          < 0.35    < 1.18
---------------------------------------------------------------------
a  Level measured during aeration of the waste-water holding pond.
b  Short-term samples during specific operations.

5.4.  Populations at Special Risk

    Although   not  strictly  an  environmental   occurrence  of
hydrazine,  the  presence  of  this  compound  in   inadequately
purified  or aged medicinal  drugs can expose  a section of  the
human  population to hydrazine.   Two drugs that  exemplify this
exposure  risk  are isoniazid  (Spinkova,  1971; Matsui  et al.,
1983;  Blair et al., 1985) and hydralazine (Matsui et al., 1983;
Blair  et al., 1985).  Hydrazine  can also be formed  during the
metabolism  of  these  drugs (Noda  et  al.,  1978;  Timbrell  &
Harland, 1979).

    Recently,  hydrazine was detected in the plasma of 8 healthy
male volunteers taking isoniazid for 2 weeks and in  the  plasma
of 8 out of 14 hypertensive patients treated with, among others,
hydralazine.   After  2  weeks  of  dosing  with  isoniazid, the
average  level  of  acid-labile  hydrazine  in  men  of  a  slow
acetylator phenotype was 2.7 times higher than in men of a rapid
acetylator phenotype (Blair et al., 1985).

6.  KINETICS AND METABOLISM

6.1.  Absorption and Distribution

    When  undiluted  hydrazine (free  base)  was applied  to the
uncovered  skin of dogs, the  compound was detectable in  plasma
within  30 seconds.  Maximum concentrations were reached 1 - 3 h
after  application.   The  concentration of  hydrazine  in blood
increased with dose (Smith & Clark, 1972).

    An  aqueous solution (700 g/litre) was administered dermally
at  a dose  of 12  mg hydrazine  (free base)/kg  body weight  to
groups of 4 rabbits by fixing a piece of fibre glass  screen  to
an  area  of  shaved  skin.   The  area  was  not  covered,  but
corrections  were  made  for evaporation  loss.   Hydrazine  was
rapidly  detectable in serum and reached a maximum concentration
of 10 mg/litre approximately 1 h after application.   The  half-
life of disappearance from serum was 2.3 h.  The apparent volume
of  distribution was determined to be 630 ml/kg body weight.  It
was  calculated that 55% of  the applied hydrazine was  absorbed
percutaneously (Andersen & Keller, 1984).

    Following  intraperitoneal  (ip)  injection of  32 mg hydra-
zine/kg  body weight in  rats or mice  (free base and  hydrazine
sulfate,  respectively),  peak  concentrations of  hydrazine  in
blood  of approximately 10 mg/litre occurred almost immediately,
and  then  the  hydrazine  disappeared  rapidly  from  the blood
(Springer  et al., 1981; Nelson & Gordon, 1982).  A half-life of
44  min was observed in the blood of the rats during the first 3
h  following exposure, followed by  a slower phase with  a half-
life of 27 h (Springer et al., 1981).  When rats were exposed to
hydrazine  vapour at concentrations  of between 0  and 40  mg/m3
(free base), the blood concentration of hydrazine increased with
exposure.  After 6 h of exposure to a hydrazine concentration of
20  -  25  mg/m3, a  blood  concentration  of 0.64  mg/litre was
measured (Dost et al., 1981).

    Hydrazine  was distributed rapidly  in most tissues  of mice
and  rats after ip  or subcutaneous (sc)  exposure.  Elimination
from these tissues also occurred rapidly (Dambrauskas & Cornish,
1964;  Nelson & Gordon, 1982; Kaneo et al., 1984).  For example,
24  h  after  the injection  of  30  mg (ip  to  mice, hydrazine
sulfate)  or  60 mg  (sc to rats,  free base) hydrazine/kg  body
weight,  less than 15% of  the hydrazine present in  the various
tissues  at  2  h  was  retained  in  these  tissues  at  18   h
(Dambrauskas  &  Cornish, 1964;  Nelson  & Gordon,  1982).   The
highest levels of hydrazine were measured in the kidneys of both
rats  (Dambrauskas & Cornish, 1964; Kaneo et al., 1984) and mice
(Nelson  & Gordon,  1982), levels  in other  tissues being  much
lower. In rats, the greater part of  sc-administered  hydrazine,
recoverable  from  tissues  and blood  (approximately  75%), was
recovered from skin and muscles (Dambrauskas & Cornish, 1964).

6.2.  Metabolism and Excretion

    A  significant part of  hydrazine (free base),  administered
sc,  ip, or  intravenously (iv),  was excreted  unchanged or  as

acetylhydrazine in the urine of dogs (McKennis et al., 1955) and
rabbits (McKennis et al., 1959).  After acid  hydrolysis,  small
quantities of 1,2-diacetylhydrazine were identified in the urine
of  rabbits, but not  in that of  dogs (McKennis et  al., 1959).
Dambrauskas  & Cornish (1964) administered 60 mg hydrazine (free
base)/kg  body weight, sc, to  mice and rats and  recovered 48.3
and  27.3% of the dose, respectively, in the urine, as hydrazine
or  acetylhydrazine, while  almost none  was left  in the  body.
Approximately 14% of an ip dose of 5 mg/kg body  weight  (hydra-
zine  hydrate) was recovered in  the urine of rats  as hydrazine
(10.3%),  acetylhydrazine  (2.2%), and  diacetylhydrazine (1.2%)
(Wright & Timbrell, 1978).  In a similar study on rats,  30%  of
sc  doses of 2.6 and 5.1 mg/kg body weight (hydrazine monohydro-
chloride)   was  recovered  in  the  urine  as  hydrazine (19%),
acetylhydrazine (10%), and small quantities of diacetylhydrazine
(Perry  et al., 1981).  When  rats were injected sc  with 9.9 mg
hydrazine  (hydrazine  sulfate),  the percentages  of  the  dose
recovered  as acetylhydrazine and diacetylhydrazine were 2.9 and
2.5%,  respectively, in 48-h urine samples (Kaneo et al., 1984).
In spite of the variation in these results, it is clear that the
major part of the hydrazine administered is not accounted for.

    Noda et al. (1985b) studied the effects of microsomal enzyme
inducers on hydrazine disposition in rats.  After iv administra-
tion of 1.2 mg hydrazine (hydrazine sulfate)/kg body  weight  to
rats,  the plasma half-life was decreased from 1.69 to 1.2 h and
1.03 h by pretreatment of the animals with rifampicin and pheno-
barbital,  respectively.   Urinary  excretion of  hydrazine  was
significantly decreased by phenobarbital pretreatment from 21.3%
to 14.6% of the dose.

      In vitro  studies  revealed  that  both  oxyhaemoglobin  in
erythrocytes  and liver microsomal  oxygenases can catalyse  the
oxidation of hydrazine to nitrogen (Clark et al., 1968; Springer
et al., 1981; Nelson & Gordon, 1982).  Diazene (C4H4N2) has been
proposed  as a probable  intermediate (Nelson &  Gordon,  1982).
Rat  liver cytochrome P-450 has been implicated in the formation
of  a free  radical intermediate  that must  be a  precursor  of
diazene during microsomal oxidation of hydrazine (Noda  et  al.,
1985a).  Tracer balance studies with 15N-labelled hydrazine have
shown  that rats and mice can convert hydrazine to nitrogen gas,
which  is excreted via the lungs.  The  results of these studies
are summarized in Table 4.


Table 4.  Tracer-balance studies with 15N-labelled hydrazine
----------------------------------------------------------------------------------------
Species  Route   Dose         Medium             Metabolites          % of     Reference
                 (mg/kg                                               dose
                 body weight)
----------------------------------------------------------------------------------------
Rat      ip      32           expired air        15N-nitrogen         25       Springer 
                 (free                                                         et al.
                 base)        urine              hydrazine,           30       (1981)     
                                                 acetylhydrazine;
                                                 acid-hydrolysable    20
                                                 derivativesa;
                                                 15N-ammonia          NDb


                              bile               hydrazine and acid-  < 1
                                                 hydrolysable            
                                                 derivatives

Mouse    ipc     32           expired air,       15N-nitrogen         30 - 35  Nelson & 
                 (hydrazine                                                    Gordon
                 sulfate)     urine              hydrazine or labile  15       (1982)     
                                                 conjugates;
                                                 acid-hydrolysable    25
                                                 derivatives
----------------------------------------------------------------------------------------
a  Excluding acetylhydrazine.
b  ND = not detected.
c  sc and iv injection resulted in minor differences in conversion.

    Nelson & Gordon (1982) reported the identification  of  some
of  the acid-hydrolysable derivatives, as shown in Fig. 1.  They
postulated that, when administered  in vivo , hydrazine is rapidly
oxidized  to nitrogen gas  by haem constituents,  including oxy-
haemoglobin  and cytochrome  P-450, and  to a  free  radical  of
hydrazine  leading to diazene, which spontaneously decomposes to
nitrogen gas.  After this initial release of nitrogen during the
first  15 - 30 min, nitrogen release is much slower, and acetyl-
ation  and carbonyl group  reactions are the  dominant processes
leading  to urinary products  (Fig. 1).  About  20 - 30%  of the
hydrazine  dose  is  expired as nitrogen gas in the first 2 h in
both  rats  and mice  (Springer et al.,  1981; Nelson &  Gordon,
1982).

Figure 1

    Approximately  25% of the hydrazine dose remains unaccounted
for.    Ammonia  was  found  in   the  blood  of  dogs   without
significantly   elevated  blood-urea  nitrogen   (Floyd,  1980).
Springer  et  al. (1981)  did not find  labelled ammonia in  the
urine  of rats exposed  to 15N-hydrazine (Table  4).  Therefore,
the  ammonia in  dogs was  probably not  derived from  hydrazine
(section  8.3.2), but was the  result of an effect  on metabolic
pathways (Floyd, 1980; Springer et al., 1981).

6.3.  Reaction With Body Components

    No  adduct formation between  hydrazine and DNA  in vivo  has
been reported (Shank, 1983). Under non-physiological conditions,
hydrazine can react with pyrimidine bases.  These reactions were
reviewed by Kimball (1977).  Indirect methylation of guanines in
DNA  following hydrazine exposure has been demonstrated and will
be discussed in section 8.5.1.

7.  EFFECTS ON ORGANISMS IN THE ENVIRONMENT

7.1.  Aquatic Organisms

    A summary of acute toxicity data is presented in table 5. It
should be  realized that  the rate  of decay of hydrazine in the
aquatic environment  depends on  the conditions  (section  4.2).
When the  concentration of  hydrazine is  not  monitored  during
exposure, it  should be  noted that  the toxic  effects observed
must have  occurred at  concentrations lower  than  the  nominal
ones, due to degradation of the compound. the increased toxicity
of hydrazine  for guppies  in soft  water at  a pH  just below 7
compared  with   the  toxicity   in  hard   water  at  a  pH  of
approximately 8,  as found  by Slonim (1977), is at least partly
explained by  the increased persistence of hydrazine in soft and
non-alkaline water.  Taking into account the decay of hydrazine,
increases  in  water  temperature  were  found  to  enhance  the
toxicity of the compound for bluegills (hunt et al., 1981).

    Teratogenicity and  toxicity screening  were reported  using
the South  African clawed  toad (Greenhouse,  1976a,b),  fathead
minnow (Henderson et al., 1981), and rainbow trout (Henderson et
al., 1983).  Eggs of  the  South  African  clawed  toad  in  the
cleavage were  exposed to hydrazine until hatching. Survival and
development into  normal larvae  occurred at  exposures below 10
mg/litre. At  10 mg/litre,  35% of the embryos were malformed at
hatching.  The   effect  was  dose-related.  Additional  studies
revealed that  teratogenic effects  appeared during  neurulation
(Greenhouse, 1976a).  When larvae  of the  South African  clawed
toad were  exposed to  1.0 mg  hydrazine/litre water, for 120 h,
all died in 24 - 48 h following exposure. No significant effects
on survival  and development were observed after exposure to 0.1
mg/litre,  the  next  lower  concentration  tested  (Greenhouse,
1976b).

    Eggs of  fathead minnows  at  the  mid-cleavage  stage  were
exposed to  hydrazine for 24 or 48 h. Embryos, exposed for 24 h,
to 0.1  mg/litre, showed  several defects,  such as  slightly or
moderately  subnormal   heart  beat,  haemoglobin  levels,  body
movement amount  of eye  pigment. From  1 mg/litre  upwards, the
responses were generally stronger; in addition, body pigment was
absent and developmental arrest was observed. Embryos exposed to
a hydrazine  concentration of  1.0 mg/litre for 48 h appeared to
have little  chance of survival. Surviving embryos showed severe
deformities and  larvae exhibited  reduced growth  (Henderson et
al., 1981).


Table 5.  Acute aquatic toxicity of hydrazine
---------------------------------------------------------------------------------------------------------
Organism                  Tempera-  pH       Hardness   Flow/  Parameter   Concentration  Reference
                          ture               (mg CaCO3  stata              (mg/litre)
                          (°C)               /litre)
---------------------------------------------------------------------------------------------------------
Bacteria

   Pseudomonas putida      20                            stat   16-h TT     0.019          Bringmann & 
                                                                                          Kühn
                                                                                          (1980)b
Protozoa

   Entosiphon sulcatum     25        6.9                 stat   72-h TT     0.93           Bringmann & 
                                                                                          Kühn (1981)b

   Uronema paraduczi       25        6.9                 stat   22-h TT     0.24           Bringmann & 
                                                                                          Kühn (1981)b

   Chilomenas paramecium   20        6.9                 stat   48-h TT     0.002          Bringmann & 
                                                                                          Kühn (1981)b

Algae

  Green algae
   (Chlorella pyrenoidosa) 23        6.8      75         stat   48-h EC50   ca.10c         Heck et al.
                                                               48-h EC100  ca.100c        (1963)d

Crustacea

  Water flea              20        8.0                 stat   24-h EC50   2.3c           Bringmann & 
   (Daphnia pulex)                                                                         Kühn (1982)
                                    8.2                 stat   24-h LC50   1.16c          Heck et al.
                                                                                          (1963)
                          20        7.1-7.2             stat   24-h LC50   0.51 and 1.01  Velte (1984)e
                                                               48-h LC50   0.16 and 0.19

Amphibia
  South African clawed
  toad  (Xenopus laevis)
  eggs                              8.2-8.7             stat   LOEL        10c            Greenhouse
                                                                                          (1976a)f
  larvae                                                stat   120-h LOEL  1.0c           Greenhouse
                                                               120-h NOEL  0.1c           (1976b)g
Table 5.  (contd.)
---------------------------------------------------------------------------------------------------------
Organism                  Tempera-  pH       Hardness   Flow/  Parameter   Concentration  Reference
                          ture               (mg CaCO3  stata              (mg/litre)
                          (°C)               /litre)
---------------------------------------------------------------------------------------------------------

Fish (fresh-water)
  Guppy  (Lebistes reti-   22-24     7.8-8.2  400-500    stat   96-h LC50   3.85c          Slonim (1977)
   culatus)                22-24     6.3-6.9  20-25      stat   96-h LC50   0.61c

  Fathead minnow
  (Pimephales promelas)    
  eggs                    21        7.0-7.5  150        flow   48-h LOEL   0.1            Henderson et 
                                                               48-h NOEL   0.001          al. (1981)h
  adults                  20                 192        stat   96-h LC50   4.5c           Cowen et al.
                                                                                          (1981)
  adults                  20        6.9                 flow   96-h LC50   5.98           Velte (1984)e


  Bluegill sunfish        23-24     7.2-8.4  240-292    stat   96-h LC50   1.08           Fisher et al.
   (Lepomis macrochirus)                                                                   (1980)
                          23-24     7.8-7.9  164        flow   96-h LOEL   0.43           Fisher et al.
                                                                                          (1980)i
                          23-24     7.1-7.9  239        stat   96-h LOEL   0.1            Fisher et al.
                                                                                          (1980)i
                          10        6.7-8.0  160-190    flow   96-h LC50   1.6            Hunt et al.
                          15.5                                             1.0            (1981)
                          21                                               1.2

  Goldfish  (Carassius               8.2-8.5             stat   48-h LC50   2.8c           Heck et al.
   auratus)                                                                                (1963)j
                          19        8.1-8.5  135        stat   24-h LC50   0.95           Proteau et al.
                                                                                          (1979)

  Roach  (Rutilus          19        8.1-8.5  135        stat   24-h LC50   0.54           Proteau et al.
   rutilus)                                                                                (1979)

  Zebra fish
  (Brachydanio rerio)
  5-day-old               26        7.8      110        stat   24-h LC50   0.75           Proteau et al.
                                                                                          (1979)
  3-month-old             20        7.6-8.2  110        stat   24-h LC50   2.03           Proteau et al.
                                                                                          (1979)

Table 5.  (contd.)
---------------------------------------------------------------------------------------------------------
Organism                  Tempera-  pH       Hardness   Flow/  Parameter   Concentration  Reference
                          ture               (mg CaCO3  stata              (mg/litre)
                          (°C)               /litre)
---------------------------------------------------------------------------------------------------------

  Green sunfish (Leptomis           8.2-8.5             stat   48-h LC50   5.1c           Heck et al.
                                                                                          (1963)j
  Large mouth bass                  8.2-8.5             stat   48-h LC50   3.6c           Heck et al.
                                                                                          (1963)j
  Channel catfish                   8.2-8.5             stat   48-h LC50   1.6c           Heck et al.
                                                                                          (1963)j
Fish (marine species)
  Stickle back  (Gaster-   14-       7.6-8.0             stat   96-h LC50   3.4c           Harrah
   osteus aculeatus)       15.5                                                            (1978)k
---------------------------------------------------------------------------------------------------------
a  Flow-through or static test.
b  TT = toxicity threshold.
c  No analysis for hydrazine during exposure was reported.
d  EC50 and EC100 for 50% and 100% growth inhibition, measured by reading optical density.
e  Soft water.
f  LOEL = lowest-observed-adverse-effect level for teratogenicity. Exposure of eggs in cleavage stage 
   until hatching.
g  LOEL = lowest-observed-adverse-effect level for lethality.  NOEL = no-observed-effect level 
   for lethality and development.
h  LOEL and NOEL = lowest-and-no observed-adverse-effect level for toxicity and teratogenicity.
i  LOEL = lowest-observed-adverse-effect level for dorsal light response (at a non-lethal concentration).
j  Standard reference water.
k  Salinity, 1.8%.
    Henderson et  al. (1983)  also exposed eggs of rainbow trout
 (Salmo gairdneri) for  48 h,  to hydrazine  in  continuous-flow
tests at  11.5 - 12 °C, a pH of 7 - 7.5, and a water hardness of
15 mg calcium carbonate/litre. During exposures up to 5 mg/litre
a dose-related  increase was observed in the incidence of poorly
fitting  jaws,  pronounced  mouth  gape,  and  absence  of  body
movement. However,  no effects were observed on mortality, heart
beat, hatching  rate, or  hatching period.  Reduced  growth  and
abnormal  development  of  larvae  were  observed  at  1  and  5
mg/litre. Poor  muscular development  and poor  bone growth were
observed; the authors postulate that this is a result of calcium
binding by hydrazine.

7.2.  Microorganisms

    The toxicity  of  hydrazine  for  a  number  of  species  of
bacteria, algae, and protozoa was measured by Bringmann (1975) &
Bringmann & Kuhn (1980, 1981). Some very low toxicity thresholds
were reported,  for example, 0.005 mg/litre for a 7-day exposure
for the algae  Scenedesmus quadricauda  and 0.00008 mg/litre for a
10-day exposure for the blue algae  Microcystis aerogenosa. This
is a very sensitive test.

    London et al. (1983) described the toxicity of hydrazine for
the soil  heterotroph  Enterobacter cloacea.  Hydrazine caused a
concentration-dependent  increase   in  the  lag  time  of  this
organism. In  a medium  containing 10  mg/litre,  this  did  not
affect the  growth rate  and final  growth yield  after the  lag
period. At 100 mg/litre, the bacteria were not viable.

    Although relatively  high  concentrations  of  hydrazine  in
water have  been recorded  as inhibiting,  either completely  or
partially, the  activities  of   Nitrosomonas,  Nitrobacter,  and
other bacteria  in culture  media (Yoshida & Alexander, 1964) in
waste-water  treatment  (Tomlinson  et  al.,  1966;  Farmwald  &
MacNaughton,  1981;   Kane  &  Williamson,  1983),  the  highest
continuously maintained tolerable level in waste water is of the
order of  1 mg/litre,  as stated  in  section  4.3  (Farmwald  &
MacNaughton, 1981).

7.3.  Plants

    Heck et  al. (1963)  studied the effects of hydrazine on the
germination of  seeds and seedling growth after application as a
hydroponic culture contaminant and an air fumigant.

    Seeds  of   summer  brush   squash  (Cucurbita pepo),  peanut
 (Arachis hypogaea),  and corn  (Zea mays)  were soaked for 48 h in
water containing  hydrazine at  levels of  between  0  and  1000
mg/litre. The temperature was 30 °C. At the highest concentra-
tion, germination of peanut and corn seed was inhibited. Seed-
ling growth  was inhibited  from 10  mg/litre  for  squash,  100
mg/litre for corn, and 1000 mg/litre for peanut.

    Sixteen-day-old seedlings of cotton  (Gossypium hirsutum)  in
a hydroponic  culture were  exposed to  hydrazine in  the growth
medium for  9 days  at concentrations  of  between  0  and  1000
mg/litre and  a temperature of between 22 and 29 °C. Plants died
within 48  h of  exposure to 300 mg/litre and within 30 h at the
higher  concentrations.   Injury  was   first  noted  as  foliar
dehydration, without  chlorosis or  necrosis, after  9  days  of
exposure to  50 mg/litre  or within  24 h  of  exposure  to  300
mg/litre or more.

    Several plants were also exposed for 4 h to hydrazine vapour
at concentrations of between 0 and 100 mg/m3 air. Species tested
were soybean  (Glycine max),  cow pea  (Vigna sinensis), pinto bean
 (Phaseolus   vulgaris),  cotton  (Gossypium   hirsutum),  endive
 (Cichorium  endivia),  alfalfa  (Medicago  sativa),  and   squash
 (Cucurbita  pepo).  Wilting  of  leaves  in  all  species  was
observed within  2 -  24 h  of exposure to 30 mg/m3, followed by
wilting of  the whole  plant. Death  occurred in pinto beans and
endive plants  at this exposure level. At higher concentrations,
plants  of  soybean  and  alfalfa  also  died.  Six  days  after
exposure, all surviving plants started to recover.

8.  EFFECTS ON EXPERIMENTAL ANIMALS

    In section  8, all doses have been expressed in terms of the
free base; however, the form of hydrazine used in each study has
been indicated when possible.

8.1.  Single Exposures

    The toxicology  of  hydrazine  has  been  reviewed  by  Krop
(1954), Clark et al. (1968), and US NIOSH (1978).

    LD50  values for rats and mice after  oral, iv, and ip expo-
sure were  not significantly  dependent on the route of exposure
and ranged  from 55 to 64 mg/kg body weight for rats and from 57
to 82  mg/kg body  weight  for  mice  (free  base  or  hydrazine
hydrate) (Witkin,  1956; O'Brien,  1964; Yaksctat, 1969; Azar et
al., 1970).  Oral LD50  values for hydrazine (hydrazine hydrate)
in guinea-pigs  and rabbits  were 26  and 35  mg/kg body weight,
respectively (Yaksctat,  1969). Dogs  and rabbits  appeared more
sensitive, LD50  values following  iv injection  being 25 and 26
mg/kg body  weight, respectively. The dermal LD50 for the rabbit
was 93 mg hydrazine (free base)/kg body weight (Rothberg & Cope,
1956; Witkin,  1956). When  doses between  96 and 481 mg/kg body
weight (free  base) were  applied to the skin of dogs, 10 out of
25 animals died within the 6-h observation period; a dose-effect
relationship was  not observed  (Smith & Clark, 1972). When rats
and mice  inhaled hydrazine  (free base) for 4 h, the LC50s were
750 and  330 mg/m3,  respectively (Jacobson et al., 1955). Death
occurred quickly  in both  species. Lethal  doses  of  hydrazine
usually induced convulsions, excitement or inactivity, and other
effects on  the central  nervous system.  Rats and mice inhaling
lethal concentrations  of  hydrazine  (free  base)  also  showed
dyspnoea (Comstock et al., 1954; Jacobson et al., 1955; O'Brien,
1964). Spontaneous  motor activity  depression was noted in rats
at ip  doses of  39 and 52 mg/kg body weight (hydrazine sulfate)
(Pradhan &  Ziecheck, 1971).  Dogs receiving a sublethal iv dose
(free base)  did not  exhibit convulsions  but showed  increased
neuromuscular activity,  salivation,  diarrhoea,  vomiting,  and
hyperventilation (Wong, 1966).

    Few pathological  changes have been reported following acute
lethal doses. Some rats that died after inhaling hydrazine (free
base), showed lung oedema with localized damage to the bronchial
mucosa (Comstock  et al.,  1954). Wells  (1908)  observed  fatty
changes in  the liver  in 24 h following sublethal doses in many
species. Fatty changes have also been observed in the kidneys of
rats (free  base or  hydrazine hydrate) (Dominguez et al., 1962;
Scales &  Timbrell,  1982).  In  rats,  accumulation  of  lipid,
swelling of mitochondria, and an increased number of microbodies
were observed  in the  liver and  in the proximal tubules of the
kidneys, 24  h after  an ip  dose of  20 or 30 mg/kg body weight
(hydrazine hydrate).  Similar changes  were observed within 1 h,
after doses  of 40  or 60  mg/kg body weight (Scales & Timbrell,
1982).  In  addition,  nuclear  and  nucleolar  enlargement  and
hypertrophy of the smooth endoplasmic reticulum were observed in
the  liver   of  rats,   2  or   more  hours   after  a   single

intraperitoneal dose of 64 mg/kg body weight (hydrazine sulfate)
(Ganote &  Rosenthal, 1968).  Studies on the mechanisms by which
hydrazine causes  these effects will be discussed later (section
8.3) together with other effects on the intermediary metabolism,
notably hypoglycaemia and lipid peroxidation, and effects on the
central  nervous   system,  such   as  an   increase  in  gamma-
aminobutyrate levels in the brain.

    In dogs  given a  sublethal dose  of hydrazine  (free base),
degeneration of  the proximal  convoluted tubules of the kidneys
was accompanied  by decreased creatinine clearance and increased
glucose reabsorption  by the  tubules. The glomerular filtration
rate was  decreased because  of decreased  renal blood flow (Van
Stee, 1965; Wong, 1966).

    In rhesus  monkeys treated  intravenously with  2.5 - 9.8 mg
hydrazine (hydrazine  sulfate)/kg,  liver  function  tests  were
generally within  normal limits  up to 72 h after dosing. A dose
of 80  mg/kg caused fatty liver, but no necrosis (Warren et al.,
1984).

8.2.  Short-Term Exposures

8.2.1.  Inhalation exposure

    In a  6-month inhalation  study, groups  of 50  male Sprague
Dawley rats,  40 female  ICR mice,  8 male  Beagle dogs,  and  4
female rhesus  monkeys were  exposed to 0.26 or 1.3 mg hydrazine
(free base)/m3  air, continuously, or 1.3 or 6.5 mg hydrazine/m3
air, for  6 h/day,  5 days/week.  Exposure  concentrations  were
monitored. Control  groups contained the same number of animals.
The exposure  regimen was  chosen in  such a way that the weekly
doses received  by the continuously exposed groups were approxi-
mately equal  to the  weekly doses  of hydrazine received by the
intermittently exposed  groups. An  increased mortality rate was
only seen  in mice  at the  2 higher  exposure levels.  In rats,
there was  a dose-related  decrease in  body weight  gain, while
body weights  of dogs  were decreased  at the  2 higher exposure
levels. In dogs, the reduced weights were at least partly due to
reduced food  consumption. Weights  of the  exposed monkeys were
comparable with those of controls. Organ weights were unaffected
by the  exposure in  rats, dogs,  and monkeys.  Organ  and  body
weights of  mice  were  not  recorded.  Central  nervous  system
effects observed  included lethargy  in mice  at  the  2  higher
exposure  levels,   and  tonic  convulsions  in  1  dog  exposed
continuously to 1.3 mg/m3. Monkeys exhibited slight eye irrita-
tion at the 2 higher exposure levels. Fatty changes of the liver
were observed  in mice  at all  exposures and  in dogs  at the 2
higher exposure  levels. The  livers of  exposed monkeys  showed
slight-to-moderate fat  accumulation.  However,  this  was  also
seen, to  some extent,  in control  animals. Livers of rats were
normal. Finally,  dogs exhibited  reduced red blood cell counts,
haematocrit, and  haemoglobin values  at the  2 higher  exposure
levels, together  with an increased resistance to osmotic haemo-
lysis at  all exposure  levels.  Haematological  variables  were

normal in  rats and  monkeys and  were not  measured in mice. In
dogs, the  effects on the liver and the haematological variables
appeared reversible (Haun & Kinkead, 1973).

    Decreases in  red blood cell count and haematocrit were also
observed in  20 female  Swiss mice  exposed to  130 mg hydrazine
(free base)/m3  air for  1 h/day,  6 days/week,  for 4 weeks. In
this study,  a decreased  osmotic resistance  to haemolysis  was
noted in exposed mice (Cier et al., 1967).

    Groups of 10 - 30 male Wistar rats were exposed to hydrazine
(free base)  at average  concentrations of 6, 18, 26, 70, or 295
mg/m3 air, for 5 days/week, 6 h/day, over periods ranging from 5
to 40  days at  the 3 highest exposure levels to approximately 6
months at  the 2  lowest  exposure  levels.  The  control  group
consisted of  10 rats.  Increased mortality  was observed at all
exposure levels  but not  in controls,  and  body  weights  were
decreased at the 3 highest exposure levels. Rats became sluggish
during the  6-month exposure,  while at  the 3  highest exposure
levels, an  initial restlessness  was followed  by a tendency to
sleep. In  some cases,  pathological examination  revealed  lung
oedema with  local damage  to the  bronchial  mucosa  at  the  3
highest exposure levels. Fatty livers were observed in many rats
after 5 days of exposure at 295 mg/m3 (Comstock et al., 1954).

8.2.2.  Other routes of exposure

    Groups of  25 male Sprague Dawley rats were dosed ip with 10
or 20 mg hydrazine (free base)/kg body weight, 5 times per week,
for 5  weeks. The  control group consisted of 15 rats. Mortality
was increased  at the  dose of  20 mg/kg body weight; 10/25 rats
died after  8 - 21 doses. Body weight was lost in a dose-related
manner; 4.4  and 25.7% of the initial body weight was lost in 10
days in  the 10  and 25  mg/kg groups, respectively. At 20 mg/kg
body weight,  rats also  displayed weakness  and lethargy, and 2
rats exhibited  convulsions. Pathological  examination  revealed
hyperaemia and  oedema in  the lungs  of 4 rats and slight fatty
vacuolation in  the liver  of 7 rats at 20 mg/kg body weight. At
both doses,  the haematocrit  values  were  maximally  decreased
after 13 injections (Patrick & Back, 1965).

    Patrick &  Back (1965)  treated 12  rhesus monkeys  ip  with
hydrazine (free  base), 5 times per week. Six monkeys received 5
mg/kg body  weight for  4 weeks; two of these monkeys received a
further 8  doses of  10 mg/kg  body weight,  followed by  4 or 5
doses of  20 mg/kg  body weight.  A group  of 6 monkeys received
only 4  or 5  doses of  20 mg/kg  body weight. The control group
consisted of 10 monkeys. No monkey died, but all exposed monkeys
showed decreased  body weights. Lethargy, weakness, and vomiting
were see  in 7 of the 8 monkeys exposed to 20 mg/kg body weight,
while tremors  were seen  in 1  of these  monkeys. Fatty changes
were observed  in the  liver, proximal  tubules of  the kidneys,
heart, and  skeletal  muscles  at  20  mg/kg  body  weight,  and
occasionally  at  5  mg/kg  body  weight.  Extensive  periportal
necrosis was found in the liver of one of the dosed monkeys. The

level of  bilirubin was  increased and  the serum  was  icteric.
Haematocrit and  haemoglobin values,  measured at the lower dose
only, dropped  slightly, relative  to control  values (Patrick &
Back, 1965).

    The pathological effects on the liver were also investigated
microscopically, in  groups of 20 - 29 male DDY mice and 10 male
Wistar rats,  after administration  of 5, 10, or 20 mg hydrazine
(free base)/kg  powdered diet, for 3 - 10 days. No animals died.
Animals of  both species exhibited weakness. Megamitochondria or
fatty vacuolation with moderately swollen mitochondria and focal
proliferation of  the smooth  endoplasmic reticulum were induced
in rats  and mice  at dose  levels of  10 and 20 mg/kg feed. The
induction of  megamitochondria was  a reversible  process (Waka-
bayashi et al., 1983). Noda et al. (1983) observed centrilobular
hepatic necrosis  in male  rabbits dosed for 5 days with between
14.6 and 32.3 mg hydrazine (hydrazine monohydro-chloride)/kg 
body weight per day, iv.

    In other  studies, hydrazine  (hydrazine hydrate)  was given
orally in  drinking-water to  albino rats  and guinea-pigs for 7
months at  levels providing  0.3, 0.03,  0.003, and 0.0003 mg/kg
body weight  per day.  At the two highest doses, adverse effects
were observed  in the  CNS (changes  in  conditioned  reflexes),
liver (increased  I131 excretion,  changes in  enzyme  activity,
protein  dystrophia),   and  blood   (symptoms  of   haemoloytic
anaemia). The dose of 0.003 mg/kg body weight was reported to be
the no-observed-adverse-effect level (Yaksctat, 1969).

8.3.  Biochemical Effects and Mechanisms of Toxicity

    All of  the studies described in this section were performed
with doses considered to be toxic.

8.3.1.  Effects on lipid metabolism

    Hydrazine  caused   a  dose-dependent  increase  in  hepatic
triglyceride levels  in rats, the threshold dose for a single ip
injection being  10 -  20 mg/kg body weight. The maximal effect,
an increase  of 7  times the control value, was observed after a
dose of  40 or  60 mg hydrazine hydrate/kg body weight. At these
dose levels,  the effect  was measurable  4  h  after  injection
(Timbrell et  al.,  1982).  Other  authors  have  also  reported
accumulation of  triglycerides in  the liver  of rats exposed to
single  doses  of  hydrazine  via  injection  routes  (Amenta  &
Dominguez, 1965a;  Clark et  al., 1970;  Lamb  &  Banks,  1979).
Several mechanisms have been proposed:

     1.   Increased  mobilization   of  free  fatty  acids  from
          adipose tissue  (particularly observed  at low plasma-
          glucose levels) leading to an increased uptake of free
          fatty  acids,   followed  by   increased  triglyceride
          synthesis in  the liver  (Trout, 1965,  1966; Clark et
          al., 1970).  This mobilization  of  free  fatty  acids
          might be  caused by  the effects  of hydrazine  on the
          sympathetic nervous  system and  on levels  of adrenal

          steroid hormone,  possibly in  response to  the  hypo-
          glycaemia induced  by hydrazine  (Amenta &  Dominguez,
          1965a).  Cooling   et  al.   (1979)   found   elevated
          concentrations  of   circulating  corticosterone   and
          decreased concentrations  of insulin  in the  serum of
          rats exposed  to  hydrazine.  Decreased  blood-insulin
          levels were  also measured in rats by Aleyassine & Lee
          (1971).

     2.   Increased  synthesis   of  triglycerides   caused   by
          increased enzymatic activity of phosphatidate phospho-
          hydrolase (EC 3.1.3.4) in hepatocytes both  in vivo  and
           in vitro  was  reported by Lamb & Banks (1979).  It has
          been suggested  that this  was a  result of  increased
          corticosterone  levels  (Cooling  et  al.,  1979).  In
          addition, Marshall et al. (1983) found increased fatty
          acid synthesis  in the  liver of  rats after hydrazine
          administration.

     3.   Triglycerides could  accumulate in  hepatocytes  as  a
          result of  a decreased  secretion of lipoproteins from
          liver to  plasma (Amenta  & Dominguez, 1965a; Clark et
          al., 1970).  This could  be explained  by a  decreased
          lipid-binding capacity  of lipoproteins  following  an
          observed alteration in the proportion of phospholipids
          and  cholesterol   (Clark  et   al.,   1970)   or   by
          increased lipid peroxidation (Di Luzio  et al.,  1973;
          Kopylova  et   al.,  1982).   The  protein  moiety  of
          lipoproteins could  also be subject to change (section
          8.3.2).

8.3.2.  Effects on carbohydrate and protein metabolism

    Rats and  dogs with starvation-induced depletion of glycogen
stores showed  rapidly declining  plasma-glucose levels  with  a
concomitant rise  in lactate  and pyruvate levels after exposure
to single intravenous hydrazine doses of 64 (free base or hydra-
zine  sulfate)   and  25   mg  (free   base)/kg   body   weight,
respectively. In  well-fed dogs, hyperglycaemia and depletion of
glycogen  stores   preceded  hypoglycaemia.  Acidosis  developed
slowly as  a  result  of  an  increased  lactate-pyruvate  ratio
(Fortney, 1966; Fortney et al., 1967; Ray et al., 1970).

    It has  been postulated  that hydrazine  inhibits  glyconeo-
genesis (Fortney,  1966; Fortney et al., 1967). This could occur
via  inhibition  of  pyridoxal  phosphate-dependent  aminotrans-
ferases and  decarboxylases. It  has been  shown that  hydrazine
interferes  with   pyridoxal   phosphate   synthesis in vitro 
(McCormick &  Snell, 1961)  and  in vivo  (Chatterjee  & Sengupta,
1980) (section  8.3.5). Inhibition  of transaminases  would also
explain the increase in free amino acids observed in the plasma,
liver, brain, and muscle of rats (Cornish & Wilson, 1968; Banks,
1970) and  in the  plasma and urine of dogs (Korty & Coe, 1968).
It could  further explain  several observations in rats, such as
the depressed  conversion  of  amino  acids  to  carbon  dioxide
(Amenta &  Dominguez, 1965b;  Dost et  al., 1971), the depressed

incorporation of  amino acids in plasma-glucose (Fortney et al.,
1967), and the enhanced incorporation of amino-labelled acids in
liver proteins, 24 h following hydrazine exposure (Banks, 1970).
Inhibition of  protein synthesis was also observed in rat livers
up to  8.5 h  after  exposure  (Lopez-Mendoza  &  Villa-Trevino,
1971).

    Hydrazine treatment  of rats  resulted in inhibited activity
of  specific  aminotransferases  and  decarboxylases  including:
liver aspartate  aminotransferase (EC  2.6.1.1) (Stein  et  al.,
1971), brain  gamma-aminobutyrate aminotransferase (EC 2.6.1.19)
and glutamate  decarboxylase (EC  4.1.1.15) (Medina, 1963; Perry
et al.,  1981), and  liver ornithine 2-oxo-acid aminotransferase
(EC 2.6.1.13)  (Roberge et al., 1971). The activity of rat liver
ornithine  decarboxylase   (EC  4.1.1.17)   increased  following
hydrazine exposure (Springer et al., 1980).

    Inhibition of  phosphoenolpyruvate carboxykinase  (ATP)  (EC
4.1.1.49), an  enzyme  involved  in  gluconeogenesis,  was  also
measured in vitro .  Hydrazine increased  the levels of  citrate,
malate, and oxaloacetate in the rat liver (Ray et al., 1970).

    Hydrazine  affects   the  urea   cycle.  Decreased  specific
activity of  ornithine 2-oxo-acid  aminotransferase,  caused  by
administration of  hydrazine to  rats (Roberge  et  al.,  1971),
provoked an  increase in  ornithine in  the liver (Banks, 1970),
brain, and  plasma (Perry  et al.,  1981). The concentrations of
citrulline and urea in the liver, kidneys, brain, and blood were
increased, as  was the  activity of  argininosuccinate lyase (EC
4.3.2.1) (Roberge et al., 1971).

8.3.3.  Effects on mitochondrial oxidation

    Swelling of  hepatic mitochondria  was observed  in rats and
mice following  hydrazine administration  (Ganote  &  Rosenthal,
1968;  Scales  &  Timbrell,  1982;  Wakabayashi  et  al.,  1983)
(sections 8.1  and 8.2.2).   in vitro   studies  on the effects of
high concentrations  of hydrazine  on the  functional status  of
mitochondria  showed  decreased  oxidation  of  keto-acids  (Von
Krulik, 1966).  Oxidative phosphorylation  measured as  the  P/O
ratio was  either not affected or decreased independently of the
hydrazine concentration  (Von  Krulik,  1966;  Fortney  et  al.,
1967). Inhibition  of beef  heart cytochrome  a by hydrazine was
also reported (Takemori et al., 1960). After administration of a
single intraperitoneal  dose  of  hydrazine  to  rats,  slightly
stimulated mitochondrial  oxidation of  succinate and  glutamate
was observed  with a  slight increase  in P/O ratio, respiration
control rate,  and phosphorylation  rate.  ATPase  (EC  3.6.1.8)
activity was  not affected  (Higgins &  Banks, 1971).  When mice
received hydrazine  (free base) in the diet (10%) for 3 days and
rats received  hydrazine in the diet (20%) for 8 days, oxidation
of succinate  and glutamate, coupling efficiency, P/O ratio, and
the activities  of ATPase (EC 3.6.1.8) and cytochrome  c  oxidase
(EC 1.9.3.1)  were slightly decreased in liver megamitochondria,
while  the  activity  of  monoamine  oxidase  (EC  1.4.3.4)  was
moderately decreased (Wakabayashi et al., 1983).

8.3.4.  Effects on microsomal oxidation

    Proliferation  of   the  smooth  endoplasmic  reticulum  was
observed in  the liver  of rats  and  mice  following  hydrazine
administration (Ganote  & Rosenthal,  1968; Wakabayashi  et al.,
1983) (sections 8.1 and 8.2.2). A single dose of 55 mg hydrazine
(free  base)/kg  body  weight  in  rats  decreased  the  hepatic
cytochrome P-450  content (Gorshtein  &  Kopylova,  1983).  Rats
exposed for  4 days  to 12  mg hydrazine  (hydrazine sulfate)/kg
body weight  per day did not show any effect on cytochrome P-450
levels in  the microsomal  fraction of the liver, but a slightly
decreased  level  of  cytochrome  b 5, inhibition  of  benzopyrene
hydroxylase (EC  1.14.14.1), and  increased parahydroxylation of
aniline (Akin & Norred, 1978).

8.3.5.  Effects on the central nervous system

    The relationship  between the  effects of  hydrazine on  the
central nervous  system, especially  the occurrence  of  convul-
sions, and  changes in  levels of  gamma-aminobutyric  acid,  an
inhibitory neurotransmitter,  in the  brain of rats and mice has
been investigated.  An increase  in the  level  of  gamma-amino-
butyric acid  was observed in the whole brain of rats after: (a)
a single  intraperitoneal dose of 51 mg hydrazine (free base)/kg
body weight  (Medina, 1963);  (b) a single intravenous dose of 5
mg hydrazine  (hydrazine sulfate)/kg  body weight  (Matsuyama et
al., 1983);  or (c)  after a  daily subcutaneous  dose of 2.6 mg
hydrazine (hydrazine  monohydrochloride)/kg body weight over 109
days (Perry  et al.,  1981). In  the whole  brain  of  mice,  an
increase was  observed following  a single intramuscular dose of
54 mg  hydrazine (free base)/kg body weight (Wood et al., 1980).
The changes  in the  concentration of this amino acid are caused
by  inhibition   of   pyridoxal   phosphate   requiring   gamma-
aminobutyrate  aminotransferase   (EC  2.6.1.19)  and  glutamate
decarboxylase (EC  4.1.1.15) (Medina, 1963; Perry et al., 1981).
Hydrazine treatment  of rats  also caused  a general  amino acid
imbalance in  the brain (Perry et al., 1981). A relationship was
suggested between  the excitable  state of  the  brain  and  the
gamma-aminobutyric acid  contents of  nerve endings  (decreased)
rather than  the whole brain contents of gamma-aminobutyric acid
(increased) (Wood et al., 1980; Geddes & Wood, 1984).

8.4.  Reproduction, Embryotoxicity, and Teratogenicity

    When groups  of 26  Wistar rats  were exposed  to 0  or 8 mg
hydrazine (hydrazine  monohydrochloride)/kg body weight per day,
sc, from  day 11 to day 20 of gestation, the exposed dams showed
a 20% decrease in body weight and 2 dams died. Reduced number of
viable fetuses  were found  in  9  dams  killed  on  day  21  of
gestation (63/172  versus 142/179 in controls), while the number
of implants per litter was not affected. The fetuses had reduced
weights and  appeared pale  and oedematous,  but did not exhibit
any major  malformations. In  the rats  allowed to deliver (12),
perinatal mortality was 100% in treated rats and 20% in controls
(Lee & Aleyassine, 1970).

    These results  agree with  those of  another study  in which
groups of  6 -  27 Fisher  344 rats received 0, 2.5, 5, or 10 mg
hydrazine (free  base)/kg body weight per day, ip, from day 6 to
day 15  of gestation.  Body weight  gains in dams were decreased
and the  number of resorptions per dam were increased in a dose-
related manner.  The differences  between  treated  and  control
animals were  statistically significant  at doses  of  5  or  10
mg/kg, but  not at  2.5 mg/kg for both variables. The numbers of
implants per  dam and  fetal weights  were not  affected at  any
dose. The incidence of litters or fetuses with abnormalities was
not significantly  increased at  any dose; however, at 10 mg/kg,
only one out of the 6 females produced a viable litter, and only
6 fetuses  were examined.  In a  subsequent study,  27 rats were
untreated and  11 rats  were treated with 10 mg hydrazine/kg per
day, during  what appeared  to be the most susceptible period of
gestation (days 7 - 9). The incidence of litters or fetuses with
abnormalities in  the 10  mg/kg group  (6 litters  out of  8;  8
fetuses out  of 16)  was significantly  higher than  that in the
control group  of the  preceeding study (8 litters out of 27; 11
fetuses out  of 181).  The abnormalities  observed  were  mainly
supernumerary and  fused ribs,  delayed  ossification,  moderate
hydronephrosis,  and   moderate  dilation  of  brain  ventricles
(Keller et al., 1982).

    Subtle postnatal  changes were  reported in the offspring of
24 female  Syrian golden  hamsters exposed orally to 0 or 170 mg
hydrazine (hydrazine  hydrate)/kg body weight on the 12th day of
gestation. The pups of exposed dams did not exhibit cleft palate
formation, but  showed effects  on the development of intestinal
brush border  enzymes. No  other  end-points  were  investigated
(Schiller et al., 1979).

    Groups of ICR mice were treated ip with 0, 4, 12, 20, 30, or
40 mg  hydrazine (free  base)/kg body weight per day, from day 6
to day  9 of  gestation. Some dams administered the highest dose
died. Body weights were reduced at doses of 12 mg/kg body weight
or more.  While at the lower doses the number of resorptions per
litter was  unchanged compared with controls, embryotoxicity was
evident at  30 and 40 mg/kg body weight. At 12 and 20 mg/kg body
weight, 17-day-old fetuses showed reduced weights, and there was
a  dose-related  increased  incidence  of  litters  with  abnor-
malities, mainly  exencephaly, hydronephrosis, and supernumerary
ribs (Lyng et al., 1980).

    Savchenkov & Samoilova (1984) studied the adverse effects on
reproductive function (fertility of females, numbers of newborn,
and resorption  of embryos)  of  female  and  male  albino  rats
exposed by  gavage to hydrazine (hydrazine nitrate) at a dose of
13 mg/kg  body weight,  once a day, for 30 days prior to mating.
The development  of the  surviving litters  did not  differ from
that of controls.

    Albino rats  (10/group and  20 controls)  of both sexes were
exposed to hydrazine (free base) (99.5% purity) in the drinking-
water at concentrations of 0.82, 0.018, or 0.002 mg/litre (0.016
mg/kg, 0.0014  mg/kg, or  0.00016 mg/kg,  respectively,  nominal

dose, assuming  water consumption  20  ml  per  day  and  animal
weights of  250 g).  The duration of the study was 6 months. The
number of animals studied and the scheme and time of mating were
not reported.  The female  rats exposed  to the  highest concen-
trations had fewer live embryos and more resorptions, as well as
pre- and post-implantation deaths, than the controls. No effects
were  observed   in   animals   administered   0.002   mg/litre.
Developmental abnormalities  were not reported in any of the 293
embryos  from   all  exposed  animals.  Destruction  of  gonadal
epithelium was  observed in  male rats  after 6  months of  oral
exposure to  hydrazine  at  concentrations  of  0.82  and  0.018
mg/litre (Duamin  et al.,  1984). In the same study, albino rats
were exposed to hydrazine (free base) at concentrations of 0.85,
0.13, or  0.01 mg/m3  (0.10 mg/kg  body weight,  0.016 mg/kg, or
0.0012 mg/kg, respectively, nominal dose, assuming inhalation of
6 litres  air per  h and  animal weights  of 200 g), for 5 h per
day, 5  days/week, for  4 months.  At the two highest concentra-
tions, embryotoxic  effects of  the same  severity were  seen as
when hydrazine was administered orally at the two highest doses.
No abnormalities  were observed  among 315  embryos. No  gonado-
toxic effects  occurred in male rats under the conditions of the
study (Duamin et al., 1984).

    Additional information  relating to  reproductive end-points
is presented in section 8.5.1 (Sotomayer et al., 1982).

8.5.  Mutagenicity and Related End-Points

8.5.1.  DNA damage

    Hydrazine was  found to  react with  pyrimidine bases  under
non-physiological conditions.  These reactions  were reviewed by
Kimball (1977).  No hydrazine-DNA  adducts have been reported to
be formed  in vivo.  A  single oral  or intraperitoneal  dose of
hydrazine (free base or hydrazine sulfate) administered to rats,
mice, guinea-pigs,  and hamsters resulted in the rapid formation
of N7-methylguanine and O6-methylguanine in liver DNA, which was
not detected  in controls (Becker et al., 1981; Quintero-Ruiz et
al., 1981;  Bosan &  Shank, 1983;  Shank, 1983). Methylation was
detectable at  toxic doses  and a  sharp increase in the methyl-
ation of  guanine  in  liver-DNA  was  observed  at  oral  doses
exceeding 60  mg/kg body weight in rats and 45 mg/kg body weight
in hamsters.  In both  species, maximum methylation approximated
80 N7-methylations and 7 O6-methylations per 100 000 residues of
guanine, 6  h after  oral exposure  to 90  mg hydrazine/kg  body
weight. Elimination of 7-methylguanine from DNA began about 24 h
after exposure with a half-life of 40 - 50 h. Elimination of O6-
methylguanine from  DNA began  about 24 h after exposure in rats
and about  50 h  after exposure in hamsters, with a half-life of
13 h and 17 h, respectively (Becker et al., 1981; Bosan & Shank,
1983). The source of the methyl group was  S -adenosyl-methionine
(Becker et al., 1981; Quintero-Ruiz et al., 1981).

    Single-strand breaks  were detected  by the alkaline elution
assay in  rat liver  cells exposed  in vitro  (Sina et al., 1983),
and in  the liver  and lung cells of mice injected ip with 50 or
100 mg  hydrazine (hydrazine  hydrate)/kg body weight (Parodi et
al., 1981).

    Hydrazine was reported to induce lambda phage in  Escherichia
 coli  (Heinemann, 1971); however, no such induction was found by
Thomson (1981),  nor did  hydrazine induce HPlcl phage in  Haemo-
 philus influenzae  (Balganesh & Setlow, 1984).

    Repair of  DNA lesions  induced by hydrazine was observed  in
 vitro.  In  the International  Collaborative Programme  for the
Evaluation of  Short-Term Tests for Carcinogenicity, 5 bacterial
DNA repair tests, using  Bacillus subtilis  or  E. coli,  were all
found to  produce weak  to medium  positive responses.  Only one
assay required rat liver microsomal fraction. The other positive
responses were  reduced  in  magnitude  by  microsomal  fraction
(Ashby &  Kilbey, 1981). Increased unscheduled DNA synthesis was
observed in  1 out of 2 tests using human fibro-blasts (Agrelo &
Amos, 1981; Robinson & Mitchell, 1981).

    No increase in unscheduled DNA synthesis was observed in the
germ cells  of mice,  16 days after a 5-day exposure to doses of
hydrazine (hydrazine  dihydrochloride) of  up to  120 mg/kg body
weight per day (Sotomayer et al., 1982).

8.5.2.  Mutation and chromosomal effects

    The results  of tests  for  gene  mutations  and  chromosome
damage induced by hydrazine or its salts are summarized in Table
6.  Hydrazine   induces   gene   mutations   and/or   chromosome
aberrations in  a variety  of  test  systems  including  plants,
phage  phi  80, bacteria,   fungi,  Drosophila  melanogaster,  and
mammalian cells  in vitro . In a few cases, microsomal activation
was an  absolute requirement  for a  positive  effect  (Gupta  &
Goldstein, 1981;  Perry &  Thomson, 1981).  In  most  cases,  an
effect could  be observed,  both  with  and  without  microsomal
activation, with a stronger effect in some tests with activation
and in  other tests  without activation.  These  inconsistencies
were evaluated  by Ashby  (1981). Some  negative results  in the
forward mutation  tests with  mammalian  cells  invitro  can  be
traced back  to the  high locus  specificity of  hydrazine  also
observed in  plants. Duamin  et al.  (1984)  observed  increased
chromosomal  aberrations  in  bone  marrow  cells  (4.12 ± 0.65%
versus 2.48 ± 0.46% in controls) of albino rats (N = 10) exposed
to hydrazine  (free  base)  at  0.85  mg/m3,  5  h  per  day,  5
days/week, for  4 months.  No  increased  incidence  of  nuclear
aberrations,  micronuclei,   dominant  lethals,  and  sperm-head
abnormalities were observed in hydrazine-treated mice (free base
or hydrazine sulfate).


Table 6.  Tests for gene mutations and chromosome damage induced by hydrazine or its salts
---------------------------------------------------------------------------------------------------------
   Test description            System description                       Result  Reference
                        Organism       Species/strain/cell type
---------------------------------------------------------------------------------------------------------
   Forward mutations    transforming    Bacillus subtilis                +       Freese et al. (1967)a
G                       DNA                                             +       Bresler et al. (1968)a

E  Forward mutations    plant          tomato                           +       Jain et al. (1968)b
                                                                        +       Chandra Sekhar & Reddy 
                                                                                (1971)b
N                                      rice                             +       Reddy & Reddy (1972)b
                                       barley                           +       Kak & Kaul (1975)b
E                                      wheat                            +       Khamankar & Jain (1978)b
                                       broad bean                       +       Vishnoi & Gupta (1980)b

   Reverse mutations    virus          phage  phi 80                     +       Chu et al. (1973)c

M  Reverse mutations    bacteria        Salmonella typhimurium  TA 1530  +       Rosenkranz & Poirier 
                                                                                (1979);Tosk et al. 
                                                                                (1979)
U
                                        Salmonella typhimurium  TA 1535  +       Purchase et al. (1978); 
                                                                                Herbold (1978); 
T                                                                               Rosenkranz & Poirier
                                                                                (1979); Bridges et al.
                                                                                (1981);d,e;
A                                                                               Parodi et al. (1981);  
                                                                                Rogan et al. (1982); 
T                                                                               Braun et al. (1984);
                                                                                De Flora et al. (1984)

I                                       Salmonella typhimurium  TA 1537  -       Bridges et al. (1981)d,e;
                                                                                Parodi et al. (1981); 
O                                                                               Rogan et al. (1982)

N                                       Salmonella typhimurium  TA 1538  +       Bridges et al. (1981)d,e
                                                                                Purchase et al. (1978);
S                                                                               Herbold (1978); 
                                                                                Rosenkranz & Poirier
                                                                                (1979); Parodi et al.
                                                                                (1981)

                                        Salmonella typhimurium  TA 100   +       Purchase et al. (1978); 
                                                                                Herbold (1978); Bridges 
                                                                                et al. (1981)d,e
---------------------------------------------------------------------------------------------------------
Table 6.  (contd.)
---------------------------------------------------------------------------------------------------------
   Test description            System description                       Result  Reference
                        Organism       Species/strain/cell type
---------------------------------------------------------------------------------------------------------
   Reverse mutations    bacteria        Salmonella typhimurium  TA 100   -       Bridges et al. (1981)d,e;
G                                                                               Parodi et al. (1981)

E                                       Salmonella typhimurium  TA 98    -, +    Herbold (1978); Bridges 
                                                                                et al. (1981)d,e; Parodi 
                                                                                et al. (1981)
N                                                                       +       Purchase et al. (1978)

E                                       Salmonella typhimurium  G 46     +       Braun et al. (1984)

   Reverse mutations    bacteria        Salmonella typhimurium  G 46     +       Röhrborn et al. (1972)
   (host-mediated       (mouse)        (NMRI)
   assay)

M  Reverse mutations    bacteria        Escherichia coli                 +       Von Wright & Tikkanen 
                                                                                (1980); Bridges et al. 
                                                                                (1981)d,e
U
                                        Haemophilus influenzae           +       Kimball & Hirsch (1975);
T                                                                               Kimball (1976)

A  Reverse mutations    fungi           Saccharomyces cerevisiae         +       Mehta & Von Borstel 
                                                                                (1981)e; Vasudeva & 
                                                                                Vashishat (1985)
T  Forward mutations    fungi           Saccharomyces cerevisiae         +       Lemontt (1977, 1978)
                                        Saccharomyces pombe              +       Loprieno (1981)e
I
   Sex-linked visibles  insect          Drosophila melanogaster          +       Jain & Shukla (1972); 
O                                                                               Shukla (1972); 
                                                                                Vijaykumar & Jain (1979)

N  Sex-linked lethals   insect          Drosophila melanogaster          +       Shukla (1972)

S  Forward mutations    hamster        ovary cells  in vitro             +       Gupta & Goldstein (1981)e
                                                                        -       Carver et al. (1981)e; 
                                                                                Hsie et al. (1981)e
                        mouse          lymphoma cells  in vitro          +       Rogers & Back (1981)
                                                                        +       Amacher et al. (1980)
---------------------------------------------------------------------------------------------------------

Table 6.  (contd.)
---------------------------------------------------------------------------------------------------------
   Test description            System description                       Result  Reference
                        Organism       Species/strain/cell type
---------------------------------------------------------------------------------------------------------
C  Breaks               plant          horse bean primary root          +       Gupta & Grover (1970)

H  Breaks, deletions,   plant          horse bean primary root          +       Heindorff et al. (1984)
   translocations
R
   Aberrationsf         plant          chick pea root                   +       Farook & Nizam (1979)
O
   Aberrations          rat            epithelial liver cells           -       Dean (1981)e
M                                       in vitro 

O  Aberrations          rat            bone marrow cells in vivo        +       Duamin et al. (1984)

S  Breaks, gaps,        hamster        ovary cells  in vitro             +       Natajaran & Van Kesteren-
   exchanges                                                                    Van Leeuwen (1981)e
O
   Sister chromatid     hamster        ovary cells  in vitro             +       MacRae & Stich (1979); 
                                                                                Perry & Thomson (1981)e
M  exchanges                                                                    
                                                                        -       Natarajan & Van Kesteren-
                                                                                Van Leeuwen (1981)e; Baker
                                                                                et al. (1983)
E                                                                               
                                       lung cells  in vitro              +       Baker et al. (1983)
                                       V-79 cells  in vitro              +       Speit et al. (1980)

   Nuclear aberrations  mouse          epithelial colon cell            -       Wargovich et al. (1983)
   (oral exposure)g
---------------------------------------------------------------------------------------------------------

Table 6.  (contd.)
---------------------------------------------------------------------------------------------------------
   Test description            System description                       Result  Reference
                        Organism       Species/strain/cell type
---------------------------------------------------------------------------------------------------------
D  Micronuclei (ip      mouse          polychromatic erythrocytes       +       Salomone et al. (1981)e
   exposure)                                                            -       Kirkhart (1981)e; 
A                                                                               Tsuchimoto & Matter 
                                                                                (1981)e
 
M  Dominant lethals     mouse          germ cells                       -       Epstein et al. (1972)
   (ip exposure)
A
      
G
 
E
------------------------------------------------------------------------------------------------------------------------
a  Inactivation of transforming DNA was observed, which was inhibited by catalase, EDTA, or nitrogen gas treatment.
b  Hydrazine appears to be a mutagen that is highly specific for certain loci.  Moreover, it not only produced mutants 
   in the M2 generation but also homozygous recessive mutants in the M1 generation (plants, raised from treated seeds).
c  Inactivation of virus observed.  Inactivation and, at lower concentrations, mutations were reduced by catalase
   treatment.
d  Hydrazine sulfate was tested in the International Collaborative Programme for the Evaluation of Short-Term Tests for
   Carcinogenicity (de Serres & Ashby, 1981).  In the summary on the assay performance of bacterial mutation assays, it
   was reported that hydrazine sulfate was mutagenic in most of a total of 20 laboratories.   However, there were
   inconsistencies in the strains in which the effect was seen and the requirements for S9 mix.   Salmonella typhimurium 
   TA 1535 was the strain in which mutagenic activity was most commonly observed, but it was also seen in all
   laboratories that used  Escherichia coli strains.  In some laboratories, hydrazine sulfate was also mutagenic in
    Salmonella typhimurium TA 100.  Two laboratories reported a marginal mutagenic activity for strain TA 98, and TA 1538
   was positive in another, while no mutagenic activity was observed with TA 1537.
e  Tested in the International Collaborative Programme for the Evaluation of Short-Term Tests for Carcinogenicity.  In
   the final assessment, it was stated that hydrazine was a genotoxic agent in bacteria, yeast, and higher eukaryotes
    in vitro .  Hydrazine did not appear to be genotoxic  in vivo in higher eukaryotic cells (de Serres & Ashby, 1981).
f  Stickiness and clumping at metaphase, bridges and fragments at anaphase, laggards, micronuclei, and delayed
   cytokinesis at telophase, tripolar spindles, prophase, and metaphase in one cell.
g  Micronuclei, pyknotic nuclei, karyorrhetic nuclei, cytolysosomes.
8.5.3.  Cell transformation

    Hydrazine  increased  the  transformation  of  baby  hamster
kidney cells  (Purchase et al., 1978; Daniel & Dehnel, 1981) and
human liver cells (Purchase et al., 1978). While Purchase et al.
(1978) observed  an increased  transformation  of  baby  hamster
kidney cells, both with and without metabolic activation, Daniel
& Dehnel  (1981) found  a much  lower  increased  transformation
frequency only  with metabolic activation. Hydrazine also caused
enhancement of  transformation  of  mouse  3T3  cells  by  Herpes
 simplex  virus  in vitro   (Johnson, 1982).   

Hydrazine induced transformation of human fibroblasts. Transformed 
cells were able to induce undifferentiated mesenchymal tumours 
after sc injections in  pre-irradiated nude mice, while control 
cells did not induce tumours (Milo et al., 1981).

8.6.  Carcinogenicity

8.6.1.  Inhalation exposure

    Groups of  100 Fischer  344 rats  of each  sex,  400  female
C57BL/6 mice,  and 200  male golden Syrian hamsters were exposed
to the  vapour of  hydrazine (free  base) for 12 months, 6 h per
day, for 5 days per week, and observed for a further 18, 15, and
12 months,  respectively (Table  7). Rats  were exposed at 0.06,
0.33, 1.3,  or 6.5  mg/m3, mice at 0.06, 0.33, or 1.3 mg/m3, and
hamsters  at  0.33,  1.3,  or  6.5  mg/m3  air.  Control  groups
contained 150  rats of  each sex,  800 female mice, and 200 male
hamsters,  respectively.  The  hydrazine  vapour  was  monitored
throughout the exposure period. A reduction in body weight gain,
seen in  exposed rats  throughout the entire study, was greatest
in males  at 6.5  mg/m3. The  mortality rate was not affected by
the exposures.  Inflammatory changes  were observed in the upper
respiratory tract  of both  sexes and in the uterus and oviduct,
especially at  the highest exposure. At 6.5 mg/m3, the incidence
of squamous  metaplasia was  increased in  the nose, larynx, and
trachea, while  the  incidence  of  epithelial  hyperplasia  was
increased in  the nose  and lungs.  An  increased  incidence  of
hyperplasia was  also observed  in the lymph nodes and uterus of
females at  6.5 mg/m3 and in the liver of females at 1.3 and 6.5
mg/m3. A  dose-related increased  incidence of benign epithelial
tumours of  the nose, mainly adenomatous polyps, was observed in
both sexes  at the  2 highest  exposures, while  at the  highest
exposure (6.5  mg/m3), the  incidence  of  malignant  epithelial
tumours was  also increased (2/98 in males and 5/95 in females).
The latency  time exceeded  87 weeks  in males  and 97  weeks in
females. The  incidence of  lung tumours  was not  significantly
increased, but,  in males,  3 bronchial  adenomas  and,  in  one
female, 1 bronchial adenoma, were observed at 6.5 mg/m3 compared
with none  in the  controls. The total incidence of adenomas and
adenocarcinomas of  the thyroid  in males was not increased, but
hydrazine exposure  at  6.5  mg/m3  increased  the  fraction  of
malignant tumours.


Table 7.  Tumour incidence in mice, rats, and hamsters following hydrazine exposure
---------------------------------------------------------------------------------------------------------
Route        Species/  Exposure   Daily dose            Tumour incidenceb           Reference
             strain    period     (mg/kg           Nose or lung        liver     
                      (months)    body weight)a  Male     Female   Male    Female
                      (life-time
                      observation)
---------------------------------------------------------------------------------------------------------
Inhalation   mouse       12         0                     8/385            -        Vernot et al. (1985)
             (C57BL/6)                                    4/378
                                    0.34c                 12/379           -
                                            
             rat         12         0            0/146    0/145    -       -        Vernot et al. (1985)
             (Fischer               0.16c        11/97    4/94     -       -
             344)                   0.8d         75/98    38/95    -       -
                                            
             hamster     12         0            1/181             -                Vernot et al. (1985)
             (golden                0.93d        16/160            -
             Syrian)                        
                                            
Oral         mouse       6 - 9      0            1/37     4/47     3/30    1/29     Biancifiori (1969,
(gavage)     (CBA)                  0.98         2/26     10/25    1/26    0/25     1970a)
                                    2.0          4/25     16/25    7/25    2/25
                                    3.9          5/25     21/24    12/25   16/24
                                    8.0          16/21    19/21    15/25   15/24
                                            
             rat         17         0            0/28     0/22     0/19    0/14     Severi & Biancifiori
             (Cb/Se)                14.6/9.7     3/14     5/18     4/13    0/18     (1968)
                                            
Oral         mouse       24 - 28    0            11/110   14/110   2/110   3/110    Toth (1969, 1972a)e
(drinking-   (Swiss)                2.0/1.6      24/50    27/50    2/50    1/50
water)                              5.1/4.6      25/50    24/50    3/50    1/50
---------------------------------------------------------------------------------------------------------
a  Calculated doses based on a weight of 300 g and a minute volume of 100 ml for rat, a weight of 35 g 
   and a minute volume of 25 ml for mice, and a weight of 140 g and a minute volume of 54 ml for hamsters.
b  - = not found; open space = not tested (nose in inhalation studies with rats and hamsters, lung in 
   the other studies.
c  1.3 mg/m3, 6 h/day, for 5 days/week.
d  6.5 mg/m3, 6 h/day, for 5 days/week.
e  Liver tumours were hepatomas (1/50 in males at both exposure levels) and angiomas.
    A slightly increased mortality rate seen in mice right up to
the end  of the study was not related to dose. Body weights were
not affected during exposure, but all exposed groups gained less
weight  than  controls  during  the  post-exposure  period.  The
incidence of  non-neoplastic lesions  was similar in treated and
control groups.  The  only  neoplastic  change  observed  was  a
slightly increased  incidence of  lung adenomas  at the  highest
exposure. A background incidence of 2 - 3% for pulmonary adenoma
in C57BL/6  mice was  reported to  be common  in the  laboratory
concerned.

    Almost double  the number of deaths occurred during exposure
in each  exposed group  of hamsters  compared with  the  control
group, but the final mortality rates were similar in all groups,
including the  control group.  During exposure  to 6.5 mg/m3 and
for 10  months after  exposure, body weights were depressed. For
several months,  an unexplained decrease in body weight occurred
in all groups, including the controls. Dose-related degenerative
changes were  observed. These  were characterized by amyloidosis
in several  organs and  issues, mineralizaton  in  kidneys,  and
haemosiderosis in  the liver.  Increased  incidences  of  senile
atrophy and  aspermatogenesis were observed in the testes at the
highest exposure  level. In addition, the incidence of bile-duct
hyperplasia was  increased at  all exposures.  The incidence  of
benign nasal  polyps was  increased at 6.5 mg/m3. The only other
striking tumours  observed were  3 adenocarcinomas, 1 leiomyoma,
and 1  papilloma in  the colon,  1 basal  cell carcinoma  in the
stomach, and  4 parafollicular  cell adenomas  in the thyroid at
6.5 mg/m3.  No such  tumours were found in the controls, but the
increased incidence  of each  tumour type  was not statistically
significant. The  authors concluded  from  these  studies  "that
hydrazine  is  capable  of  inducing  nasal  tumours,  primarily
benign, in rats and hamsters after 1-year intermittent exposure"
(Vernot et al., 1985).

8.6.2.  Oral exposure

    The oral  carcinogenicity studies  on  hydrazine  have  been
either preliminary  or  limited  in  scope  (inadequate  limited
histopathology, use of one dose or one drinking-water concentra-
tion, small  treatment groups,  lack of  adequate controls,  and
treatment of  only one  sex); therefore,  only the more relevant
studies have  been described  in this section. Most studies have
concentrated on various mouse strains.

    Groups of  approximately  25  CBA/Cb/Se  mice  of  each  sex
received, by  gavage, 150  daily doses  of hydrazine  sulfate in
water, equivalent  to 0.03,  0.07, 0.14, or 0.28 mg hydrazine in
25 weeks  (these doses  are expressed  in Table  7 as 0.98, 2.0,
3.9, or  8.0 mg/kg  body weight).  The animals were observed for
their life-time.  Control groups  containing  30  males  and  29
females were not treated. Liver, lung, various endocrine glands,
and  tissues   suspected  of   having  lesions   were   examined
microscopically. No statistical analysis was reported. No deaths
occurred during  the exposure  period, but  later the  mortality
rate was  increased in  animals that  had been  exposed daily to

levels of  2.0 mg/kg upwards. Brown degeneration of the adrenals
in treated  females was  mentioned as  a  marked  non-neoplastic
lesion.  An   apparent  dose-related   increased  incidence   of
hepatocarcinomas was  observed in  male  and  female  mice.  The
average latency  time for  this tumour  did not  decrease as the
dose increased  (Biancifiori,  1970a).  The  historical  control
incidence of hepatocarcinomas in the laboratory concerned was 8%
(Severi &  Biancifiori, 1968). Multiple pulmonary tumours, which
were  also   observed,   are   described   in   another   report
(Biancifiori, 1969).

    In this  report  (Biancifiori,  1969),  the  3  lowest  dose
groups, containing  21 -  26 males  and 21  - 25  females,  were
treated in  the same way as in the study above. The data for the
control group  and the  highest  dose  groups  were  taken  from
earlier reports (Biancifiori et al., 1964; Severi & Biancifiori,
1968). The  untreated control  groups contained  37 males and 47
females. The  highest dose group comprising 21 mice of each sex,
received  250   daily  doses   of  hydrazine  sulfate  in  water
equivalent to 0.28 mg hydrazine in 36 weeks. In the 1969 report,
the treatment  schedule was  reported to  be 150  daily doses of
0.28 mg  hydrazine in  25  weeks,  which  was  contrary  to  the
original data.  Lungs with  trachea,  liver,  various  endocrine
glands, and  other tissues  suspected  of  having  lesions  were
examined microscopically. No deaths occurred during the exposure
period, but  the mortality  rate after  the treatment period was
increased from a dose level of 2.0 mg/kg per day upwards. Common
non-neoplastic lesions  in the liver at 0.28 mg per day included
areas  of   diffuse   cell   regeneration.   Necrosis,   nodular
regeneration, sclerosis,  and bile-duct  proliferation were also
observed.  The   occurrence  of   hepatomas  has   already  been
discussed. The  incidence and  multiplicity of pulmonary tumours
were increased  at all dose levels in an apparently dose-related
manner and  more so  in females  than in  males (Table  7).  The
average latency  time for  these tumours  was  also  shorter  in
females than  in males. At the highest dose level, approximately
80% of the tumours were characterized as adenomas in both sexes,
the  remainder  being  described  as  "anaplastic  adenomas  and
adenocarcinomas" (Biancifiori, 1969).

    Induction of  lung tumours  by hydrazine  sulfate after oral
exposure by  gavage was  also reported  in other  mouse  strains
(Milia et  al., 1965;  Roe et  al., 1967;  Kelly et  al.,  1969;
Biancifiori, 1970b;  Bhide et  al., 1976;  Maru &  Bhide, 1982).
Liver  tumour   induction  was  reported  in  BALB/c/Cb/Se  mice
(Biancifiori, 1970b).

    Severi &  Biancifiori (1968)  also exposed  14 male  and  18
female Cb/Se  rats, by  gavage, for  68 weeks, to daily doses of
hydrazine sulfate in water, equivalent to 4.4 mg hydrazine (14.6
mg/kg body  weight) per  day for males and 2.9 mg hydrazine (9.7
mg/kg) per  day for  females. Controls (28 males and 22 females)
were not treated. The animals were observed for their life-time.
Lungs, liver,  and  other  organs  showing  gross  lesions  were
examined microscopically.  No statistical analysis was reported.

Exposed rats  showed  an  increased  mortality  rate.  Pulmonary
tumours, adenomas,  and adenocarcinomas  were observed  in  both
sexes (Table  7). Carcinomas  (2) and spindle cell sarcomas (2),
observed in  the livers  of exposed  males, were not seen in the
controls.

    Groups of  23 and  85 golden hamsters of both sexes received
hydrazine sulfate  by gavage  as 60  and 100 daily doses, equiv-
alent to  0.74 and  0.68 mg  hydrazine over  15  and  20  weeks,
respectively. The  control group  contained 56 hamsters. Animals
were observed  for their  life-time and  examined  as  described
above for  rats. The  mortality rate  increased in an apparently
dose-related manner,  and toxic effects were observed in treated
animals (liver  lesions, reticuloendothelial cell proliferation,
cirrhosis, bile-duct  proliferation, degenerative  fibrous cells
in hyalinized tissue). No tumours were observed, but, because of
toxic effects,  the treated  animals were  not observed  for the
same period of time as the controls (Biancifiori, 1970a).

    Groups of 50 Swiss mice of each sex received doses of hydra-
zine sulfate in drinking-water, equivalent to 0.056 mg hydrazine
(2 mg/kg  body weight,  males; 1.6  mg/kg, females)  per day for
their life-time  up to  a maximum  of 113 weeks (Toth, 1972a) or
0.18 mg (5.1 mg/kg body weight) per day (males) and 0.16 mg (4.6
mg/kg) per day (females) for a maximum of 95 weeks (Toth, 1969).
The untreated control group, containing 110 animals of each sex,
was tested  concurrently with  the groups receiving 0.16 or 0.18
mg per  day, but not with those receiving 0.05 mg per day (Toth,
1969). Liver,  kidneys, spleen,  lungs, and  organs  with  gross
lesions were  examined microscopically.  No statistical analysis
was reported. Drinking-water solutions containing hydrazine were
prepared  3  times  per  week.  There  was  no  indication  that
hydrazine concentrations  were measured  in the solutions during
the studies.  At the  highest dose  level, body weights were not
affected, but  the mortality  rate  in  females  was  increased.
Numerous lung  tumours  were  observed  in  both  sexes  with  a
comparable incidence  (Table 7) and degree of malignancy at both
dose levels.  The average  latency  time  for  this  tumour  was
decreased at  both dose  levels. At  the high  dose  level,  the
latency period for malignant lymphomas, which are characteristic
for the  strain, and  the incidence  of adenocarcinomas  of  the
mammary gland appeared to be decreased.

    Fifty Syrian  golden hamsters of each sex also received, for
their life-time,  up to  a maximum of 110 weeks, doses of hydra-
zine sulfate  in drinking-water, equivalent to 0.57 mg hydrazine
per day.  Untreated non-concurrent  control groups contained 100
hamsters of each sex. The protocol was similar to that described
above for  rats. Body  weights of exposed hamsters were slightly
reduced, but no tumours or other effects were noted. The authors
considered that  there was no treatment-related tumour incidence
and that  the mortality  rate was  not affected by the exposure,
though the  mean survival  period was  slightly  reduced  (Toth,
1972b).

    Groups of 34 male and 29 female Swiss mice were administered
hydrazine sulfate  by gastric  intubation at doses equivalent to
0.27 mg  hydrazine per mouse per day, 5 days per week, for their
lifetime. Lung  adenocarcinomas occurred  in 30  out of  34 male
mice and  in 21  out of 29 female mice compared with 1 out of 20
controls. The  earliest  tumour  appeared  after  14  months  of
exposure.  An   increased  incidence  of  lung  tumours  (20/22)
occurred  in  F1  animals,  which  were  obtained  from  treated
mothers, and  received hydrazine  sulfate post  weaning from the
age of 11 weeks. No control mice were mated. An increase in lung
tumours (16/35) was also observed in F2 animals obtained from F1
animals  that   had  been   treated  with  hydrazine  throughout
gestation and lactation (Menon & Bhide, 1983).

9.  EFFECTS ON MAN

9.1.  Poisoning Incidents

    Several incidents  of systemic poisoning have been reported,
mainly showing  effects on  the central nervous system, respira-
tory system, and stomach.

    After a  laboratory technician  had drunk 20 - 30 ml of a 6%
aqueous  solution  of  hydrazine  (free  base),  he  immediately
vomited. Four  hours later, weakness, somnolence, and arrhythmia
were observed.  Laboratory findings  showed a slight but persis-
tent leukocytosis. The serum-albumin fraction was decreased with
an  increase  in  the  fraction  of  globulin.  Two  days  after
exposure, slightly elevated body temperature and a few red blood
cells  in  the  urine  were  noted,  while  the  patient  showed
irregular breathing.  Five days  after exposure, the patient had
recovered (Drews et al., 1960).

    A case  was reported  of a  man who drank between a mouthful
and  a   cupful  of   hydrazine  in  concentrated  solution.  He
immediately vomited,  became unconscious,  and flushed. Vomiting
ceased about  12 h  after admission to the hospital. The patient
showed sporadic  violent behaviour  and later  developed  ataxia
with a  lateral nystagmus,  a decreased  sense of vibration, and
paraesthesia in  the arms  and legs.  Oliguria was  also  noted.
Pyridoxine treatment was administered, but it was not clear from
the report  whether he  benefited from this. The patient's final
condition was not reported (Reid, 1965).

    A 24-year-old  man accidentally  ingested  "a  mouthful"  of
hydrazine  and   immediately  became  confused,  lethargic,  and
restless. On admission to hospital, a complete chemistry profile
was normal, but, 3 - 4 days later, hepatotoxicity was evident as
indicated by  elevated levels of aspartate amino-transferase (EC
2.6.1.1),  lactate   dehydrogenase  (EC   1.1.1.27),  and  total
bilirubin. At this time, the patient was treated with pyridoxine
and recovered  completely within  5 days. Peripheral neuropathy,
however, developed  subsequently, which resolved over the next 6
months. The  authors attributed  this neuropathy to the megadose
pyridoxine therapy (Harati & Niakan, 1986).

    Another man  sustained a  chemical burn during an industrial
hydrazine explosion.  Exposure occurred  probably both  via  the
skin and by inhalation. The burns on his skin covered 22% of the
body surface. On admission to the hospital, the neuro-
logical status  of the  patient  was  normal  but,  14  h  after
exposure, he  became comatose. When the coma persisted for 60 h,
he was  treated with  pyridoxine, and the neurological disorders
cleared within  the next  12 h. Other findings were persistently
elevated   glucose    levels,   haematuria,    and   respiratory
difficulties.   Several    biochemical   indicators   of   liver
malfunction were elevated from day 3 after exposure and returned
to normal levels over the next 5 weeks (Kirklin et al., 1976).

    Two men  were exposed  to Aerozine  50 vapour (50% hydrazine
and 50%  1,1-dimethylhydrazine by  volume) via  a leak in a fuel
line. The first man was exposed for about 90 min via a defective
gas mask.  He reported  headache, nausea, and a shaky feeling, a
sensation of  burning of  the face, a sore throat, and tightness
in the  chest. The  second man  had inhaled  the vapour  3 times
before evacuation  from the contaminated area. He was dyspnoeic,
trembling, and  weak. Both  men  showed  neurological  disorders
including twitching  of extremities  and clonic movements in the
first  victim  and  hyperreactive  reflexes  in  both  men.  All
symptoms cleared  after treatment with pyridoxine. From clinical
signs, it  was concluded that pulmonary oedema developed in both
men and  was treated successfully. Four other cases of poisoning
by Aerozine after a spill were mentioned in this report. These 4
men showed nausea and vomiting. Both symptoms disappeared within
20 min following pyridoxine treatment (Frierson, 1965).

    One case  of systemic  lupus erythaematosus-like disease due
to occupational  exposure to  hydrazine  (free  base)  has  been
described. The  patient, a  laboratory technician, had recurrent
episodes of  joint pain, photosensitive rash, fatigue, and fever
following hydrazine  exposure. A  challenge patch test suggested
that hydrazine  caused the  illness. On  the basis  of  detailed
examinations of  the patient  and her  family, it  was concluded
that hydrazine  could cause  the disease  in  a  person  with  a
genetic predisposition.  Some of  the genetic factors identified
were slow  acetylation phenotype,  HLA DR2,3,  and immune system
responsiveness such  as antinuclear  antibodies,  antibodies  to
single-stranded and  native  DNA,  and  inhibition  of  pokeweed
mitogen-stimulated immunoglobulin  G  synthesis  in  lymphocytes
(Reidenberg et al., 1983).

9.2.  Occupational Exposure

9.2.1.  Inhalation exposure

    One case  was reported  of a  man who  had handled hydrazine
(hydrazine hydrate)  once a  week for an unknown number of hours
over a  period of  6 months. In simulated conditions, only 0.071
mg hydrazine/m3 air was measured, but probably skin exposure had
also occurred.  The man  experienced conjunctivitis, tremor, and
lethargy after  each exposure.  Following the  last exposure, he
was feverish,  vomited, and  showed diarrhoea.  In a hospital, 6
days  later,   many  disorders   were   noted:   conjunctivitis,
stomatitis, arrhythmia,  upper abdominal pain, enlarged abdomen,
icterus, a tender and palpable liver, black faeces, incoherence,
and oliguria.  X-ray examinations  showed pleural  effusion  and
lung shadowing. Laboratory findings comprised elevated bilirubin
and creatinine  levels in  the blood,  and protein and red blood
cells in  urine. Treatments  administered included haemodialysis
and B-vitamins,  which brought  only temporary  relief. The  man
died  21   days  after   the  last  exposure.  Autopsy  revealed
pneumonia, severe renal tubular necrosis and nephritis, and mild
hepatocellular damage (Sotaniemi et al., 1971).

9.2.2.  Skin and eye irritation; sensitization

    Two cases  of skin  irritation (Frierson,  1965; Kirklin  et
al., 1976)  and one  case of  eye irritation  (Sotaniemi et al.,
1971) have  already  been  cited  in  sections  9.1  and  9.2.1,
respectively. Dermatitis  of the  hands without systemic effects
was observed  in 2 men who were occupationally exposed to hydra-
zine hydrate over a period of 5 months. Both men had had similar
experiences previously,  after  handling  of  hydrazine  hydrate
(Evans, 1959). No patch tests were carried out, but the allergic
nature of  the contact  dermatitis that  can develop  after skin
exposure to  hydrazine, has  been reported  earlier. In 1959, an
outbreak of  dermatitis was  reported among  12 out of 34 female
workers in a factory where hydrazine hydrochloride was used as a
solder flux.  Four months  after the  use of the solder flux had
stopped, 6  out of  12 workers  showed strong positive reactions
towards hydrazine  sulfate, while  30 controls  did not show any
reaction (Frost  & Horth,  1959). In  an electronics  plant,  35
workers, constituting  half the  work force,  developed  contact
dermatitis   from    a   solder    flux   containing   hydrazine
hydrochloride, over  a period  of 5  years. The symptoms did not
reappear when contact with hydrazine was avoided. Patch tests on
5 female  workers of  this group  were all  clearly positive for
hydrazine fluxes,  while 3  controls did  not react  (Wheeler et
al., 1965).  Another 7  workers in  a chemical  workshop,  where
solder flux  containing hydrazine hydrochloride was used, showed
allergic contact  dermatitis towards hydrazine, as did 5 workers
in a pharmaceutical firm producing isoniazid. The results of the
patch tests  were strongly  positive for  the 12 subjects, but a
control group was lacking (Zina & Bonu, 1962). Hydrazine induced
allergic contact  dermatitis in  4 men  when used as a corrosion
inhibitor (Schultheiss, 1959; Hovding, 1967; Von Keilig & Speer,
1983). A  negative control group was tested in only one of these
studies (Hovding,  1967). Allergic  contact dermatitis developed
in 15  workers in  2 industries  producing hydrazine sulfate. In
one of  these industries, patch tests on 15 workers were clearly
positive for hydrazine, while 13 controls from the same industry
did not  show any  reaction.  Symptoms  did  not  reappear  when
contact with  hydrazine sulfate  was avoided  (Brandt, 1960). In
the other  industry, 10  persons produced  a  positive  reaction
towards hydrazine.  No negative  controls were tested (Sonneck &
Umlauf, 1961).  Two cases  of allergic  contact dermatitis  were
reported following  exposure to hydrazine in stain removers with
strong positive  reactions towards  the chemical in patch tests.
Five controls  did not react (Van Ketel, 1964). Systemic effects
were not noted in any of these studies.

    Cross  sensitization   to  hydrazine  derivatives,  such  as
isoniazid,  phenylhydrazine,   and  hydralazine,  was  found  by
several investigators (Schultheiss, 1959; Zina & Bonu, 1962; Van
Ketel, 1964; Hovding, 1967; Von Pevny & Peter, 1983).

9.2.3.  Mortality studies

    The causes  of death  in  a  cohort  of  427  male  workers,
employed for  a minimum of 6 months in a hydrazine manufacturing
plant between  1945 and  1971, were  studied retrospectively and

followed until  July 1982.  The plant ceased production in 1971.
The men  were divided according to 3 categories of exposure. The
first category  contained 78  men who might have been exposed to
concentrations of  hydrazine ranging  from 1.3  to 13 mg/m3 air.
Categories 2 and 3 (a total of 375 men) included those who might
have been  exposed to  concentrations between  0.6 and 1.3 mg/m3
and those who had little or no exposure, respectively. A further
subdivision in the first category distinguished between men with
more than 10 years since the first exposure and those with less.
Some men  were covered by more than one category. The cohort was
also exposed  to other  unspecified organic chemicals. The total
number of  deaths in  406 men who could be traced was 49 against
61.47 expected.  Five men  died  from  lung  cancer  against  an
expected 6.65.  Two of  these men  belonged to  the most  highly
exposed category.  Another 7 cases of cancer were detected (9.27
expected). Further details were not given, except for the remark
that no  nasal tumours were involved. The authors noted that the
number of  men exposed  to hydrazine in this study was small. It
was concluded  that the  results were  encouraging  in  that  no
obvious hazard had yet appeared. A note of caution is introduced
by the  observation of  2 deaths from lung cancer in men who had
first been  exposed in  the heaviest category more than 10 years
previously against 1.61 expected (Wald et al., 1984). The cohort
is being followed up.

    A seemingly  unusually high  incidence of myocardial infarc-
tion prompted  further study  among workers  in a plant manufac-
turing hydrazine.  The population  at risk  was limited to every
on-line hydrazine  worker who  had worked  for 3  months or more
between 1953  and 1978. The number of man years at risk was 534,
and  the   average  employment   period  was  8  years.  Only  a
superficial examination  of  the  population  at  risk  and  the
working environment  was completed. Reference data were provided
by the  US Air  Force men's  rates for  the years 1975-77 and by
men's rates  from a  study over  the past  30 years  by  the  US 
National Heart  Institute (Framingham  study). There was a close 
compar ison between  the 2  sets of reference data. Rates of 
occurrence of myocardial  infarction (death and non-death) per 
thousand men per year  within 5-year age groups were calculated. 
A total of 5 cases of  myocardial infarction,  concurrent with 
the employment period, were  identified  among  the  hydrazine  
workers.  Their average employment period was 16 years. A total 
of 1.2 cases was expected. The  difference is  highly significant  
statistically. Four additional  cases were  identified in ex-
hydrazine workers. However, as it was impossible to trace all 
ex-hydrazine workers, the population  at risk  was limited  to 
the "concurrent cases". The author  warned that  the findings 
should be treated with due caution because  of the  small 
numbers  involved. He also stated that the strength of the 
findings rendered a negative hypothesis almost untenable without 
further investigation into the cause of the adverse effect found 
(Hamill, 1978). 

    The Task  Group recognized that exposure concentrations were
not reported  and that  there was no indication that confounding
variables, e.g.,  smoking history  or exercise  habits, had been
taken into account.

10.  EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT
  
10.1.  Evaluation of Human Health Risks

    Exposure of  human beings to hydrazine may occur occupation-
ally or  accidentally, through  the ingestion of hydrazine-based
drugs, or  through the  use of  tobacco. Despite the high react-
ivity  of  this  compound  and  its  wide  industrial  use,  few
systematic studies  have been carried out on its adverse effects
on man.

    Hydrazine is  rapidly absorbed  through the skin, lungs, and
gastrointestinal tract  and rapidly  distributed throughout  the
body (section 6).

    In cases  of acute human poisoning, vomiting, severe irrita-
tion of  the respiratory tract with the development of pulmonary
oedema, central nervous system depression, and hepatic and renal
damage have been reported. Data are not available from which the
levels of  hydrazine inhaled  can be estimated in cases of acute
poisoning by  the respiratory  route. However,  from reports  of
poisoning by  the oral  route, it would appear that ingestion of
amounts of  the order  of 20  - 50 ml causes severe intoxication
and may  be lethal (section 9.1). It is not possible to estimate
a no-observed-adverse-effect  level  from  the  available  human
data.

    Most of  the effects  in human  beings exposed  to hydrazine
have also  been observed  in experimental  animals. In addition,
loss of  body weight,  anaemia, hypoglycaemia,  and fatty  liver
have frequently  been reported.  Fatty liver in mice and reduced
growth in  rats were  reported when  the  animals  were  exposed
through inhalation  to the  lowest (0.26  mg/m3) of  three  dose
levels. Monkeys  and dogs  were unaffected at this dose. In only
one study,  a no-observed-adverse-effect  level of 3  µwg/kg was
reported, when  hydrazine was  administered by the oral route to
rats. No data are available on the basis of which a no-observed-
adverse-effect level  by inhalation  can be established (section
8.2).

    Embryotoxicity, fetotoxicity,  and minor fetal abnormalities
were observed  in rats  and mice  exposed to  hydrazine at doses
toxic for  the mother.  At such  doses, perinatal  mortality  is
high. These  effects may  also occur  at doses  just  below  the
maternally toxic  dose (section  8.4). No  data are available on
the effects  of hydrazine  on the human fetus. In the absence of
human data,  it would  be prudent to assume that hydrazine might
have adverse  effects on  the human  embryo or fetus at exposure
levels approximating  those producing  toxicity for  the mother.
Such levels  may occur  during accidental  spillage but would be
unlikely to occur in the ambient environment because atmospheric
concentrations are low.

    Skin and  eye irritation  have been observed in human beings
who have  come into  contact with  hydrazine, but  the data  are
insufficient  to   establish  a   no-observed-effect  level  for

irritation. Hydrazine  is a  strong skin  sensitizer in  man and
cross-reacts with  hydrazine derivatives (section 9.2.2). Slight
eye irritation  was observed  in monkeys at hydrazine concentra-
tions of 1.3 and 6.5 mg/m3, but none occurred in animals exposed
to 0.26  mg/m3 (section  8.2.1). No  skin irritancy  studies  on
animals have been reported.

    The available  data indicate  that  hydrazine  induces  gene
mutations and  chromosome  aberrations  in  a  variety  of  test
systems including  plants, phages, bacteria, fungi,  Drosophila,
and  mammalian   cells  in  vitro.  Hydrazine  induced  indirect
alkylation in the liver DNA of rodents after  in vivo  exposure to
toxic doses,  and it also caused DNA damage  in vitro .  Hydrazine
transformed human  and hamster  cells in vitro.  No  increased
unscheduled DNA synthesis was observed in the germ cells of mice
  in vivo . It did not induce chromosome aberrations, micronuclei,
or dominant lethals in mice  in vivo , but chromosomal aberrations
were reported in rats  in vivo  (section 8.5).

    Hydrazine vapour  induced nasal  tumours, most of which were
benign, in  F-344 rats  and Syrian  golden  hamsters,  after  12
months of  treatment and  life-time observation. At the exposure
levels at  which most  of the tumours occurred, there were signs
of severe  mucosal  irritation.  In  several  studies  on  mice,
hydrazine induced  an increased  incidence of pulmonary tumours,
when administered  by the  oral route. Hepatic tumours were also
reported in  two studies.  In some of the studies, the pulmonary
tumour incidence  was related to the dose administered. Although
in these  reports there  is little  information about  the toxic
effects of  the compound,  it is  probable that the doses admin-
istered in  some of  the studies  were at,  or near,  the  toxic
levels. No tumours were observed in hamsters treated orally with
hydrazine (section  8.6). On  the basis  of the  carcinogenicity
studies  on   experimental  animals,   there  is  evidence  that
hydrazine is  an animal carcinogen. Human data are inadequate to
assess its carcinogenicity in man. In the absence of human data,
and taking  into account  the mutagenicity  data as  well as the
carcinogenicity data in animals, it would be prudent to consider
hydrazine as  a possible  human carcinogen.  Thus,  exposure  to
human beings should be kept as low as feasible.

    Since measurable  levels are not normally encountered in the
general environment,  it can  be concluded that, except in cases
of accidental  exposure, hydrazine  does not  pose a significant
practical hazard for the general population.

10.2.  Evaluation of Effects on the Environment

    Hydrazine can be released into the atmosphere during venting
operations, storage,  and transfer.  The total emission has been
estimated  to   be  nearly   0.01%  of  the  hydrazine  produced
(production > 35 000 tonnes in 1981). Accidental discharges into
water, air,  and soil  can result  from bulk  storage, handling,
transport, and improper waste disposal. Evaporation of hydrazine
after a  spill can generate an atmospheric concentration as high
as 4 mg/m3, 2 km downwind.

    Hydrazine is  degraded rapidly in air through reactions with
ozone, hydroxyl  radicals, and nitrogen dioxide. In water, it is
degraded rapidly,  especially under  aerobic conditions,  and in
the presence  of organic  material and/or  in alkaline  or  hard
water. It is more persistent in soft, metal-free water. In soil,
it is  adsorbed and  decomposed on  clay surfaces, under aerobic
conditions. However,  available data  are inadequate to describe
the nature of hydrazine behaviour in the soil.

    Because  of  the  rapid  degradation  of  hydrazine  in  the
environment, measurable levels are not normally encountered.

    Hydrazine can  be toxic  for aquatic  life, even at very low
concentrations. Fish  species showed LC50 values of between 0.54
mg/litre (roach)  and 5.98 mg/litre (fathead minnow). Nitrifying
bacteria in  activated sludge  are inhibited by hydrazine levels
higher than  1 mg/litre.  Some  other  microorganisms  are  more
sensitive and  show toxicity thresholds at levels reported to be
as low as 0.00008 mg/litre.

    Hydrazine in  both air  and water  is toxic  for plants;  in
water, it can inhibit plant germination.

    On the basis of these data, it can be concluded that hydra-
zine may present a significant hazard for the aquatic environ-
ment and plant life.

11.  RECOMMENDATIONS FOR FURTHER STUDIES

1.  Dose-response studies pertaining to:
    (a) DNA alkylation (adduct identification);
    (b) damage of nasal epithelium; and
    (c) pulmonary effects.

2.  Skin sensitization  studies with  focus on  cross-reactivity
    with hydrazine derivatives.

3.  Dose-response studies  on sensitive,  commercially important
    fish species and their food supplies.

4.  Metabolic studies in conjunction with effects on DNA.

5.  Dermal initiation-promotion studies.

6.  Reproduction toxicity studies in sensitive rodent species at
    continuous low exposure levels.



12.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES


    The International Agency for Research on Cancer (IARC, 1982)
considered that,  while the  evidence for the carcinogenicity of
hydrazine for  human beings  was inadequate,  evidence  for  its
carcinogenicity for  animals and  for its activity in short-term
tests was  sufficient to  conclude that  hydrazine  is  probably
carcinogenic for human beings.



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    See Also:
       Toxicological Abbreviations
       Hydrazine (HSG 56, 1991)
       Hydrazine (ICSC)
       Hydrazine (IARC Summary & Evaluation, Volume 71, 1999)