J JO.
                                                   FINAL DRAFT
        United swts                                    ECAQ-CIN-G1Q5
        Environm*nul Protection
        Research  and
        Development
       HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
       FOR HYDRAZINE
        Prepared for
       OFFICE OF SOLID WASTE AND
       EMERGENCY RESPONSE
        Prepared by
        Environmental Criteria and Assessment Office
        Office of Health and Environmental Assessment
        U.S.  Environmental Protection Agency
        Cincinnati, OH  45268


                   DRAFT: DO NOT CITE  OR QUOTE


                          NOTICE

   This document Is a preliminary draft.  It has not been formally released
by the  U.S. Environmental Protection Agency and should not at this stage be
construed to represent Agency policy.  It 1s being circulated for comments
on Us technical  accuracy and policy Implications.

   '                    HEADQUARTERS LIBRARY
                       ENVIRONMENTAL PROTECTION AGENCY
                       WASHINGTON, D.C. 20460

-------
                                  DISCLAIMER
    This report  Is  an external  draft  for  review purposes only  and  does  not
constitute  Agency  policy.   Hentlon of  trade  names  or  commercial  products
does not constitute endorsement or recommendation for use.
                                      11

-------
                      Office  files  are
                      aquatic   life  and
                        The  literature
                       are  Included  In
                                    PREFACE

    Health  and  Environmental  Effects Documents (HEEDs) are  prepared  for  the
Office  of  Solid  Waste and Emergency Response  (OSMER).  This document series
Is  Intended  to support  listings  under  the Resource Conservation and Recovery
Act  (RCRA)  as  well  as  to  provide  health-related  limits and  goals  for
emergency   and   remedial   actions   under   the  Comprehensive  Environmental
Response,   Compensation  and   Liability   Act   (CERCLA).    Both   published
literature  and  Information  obtained  for  Agency  Program
evaluated  as  they pertain  to  potential  human   health,
environmental  effects  of  hazardous  waste  constituents.
searched  for  In  this  document  and  the  dates   searched
"Appendix:  Literature Searched."  Literature  search material  Is  current  up
to  8  months  previous to the  final draft  date listed on   the  front  cover.
Final  draft  document  dates  (front  cover)  reflect  the date  the document  Is
sent to the Program Officer  (OSWER).

    Several  quantitative  estimates  are   presented  provided  sufficient data
are  available.   For   systemic   toxicants,   these  Include:  Reference  doses
(RfOs)  for chronic and  subchronlc exposures  for both the  Inhalation and oral
exposures.   The  subchronlc  or  partial  lifetime  RfD, Is an estimate of  an
exposure  level  which would  not  be  expected  to cause adverse  effects when
exposure occurs  during  a  limited time  Interval  I.e., for an  Interval  which
does  not  constitute  a  significant   portion  of the  Hfespan.   This  type  of
exposure estimate  has not been  extensively used,  or rigorously  defined  as
previous risk assessment  efforts  have  focused  primarily on  lifetime exposure
scenarios.   Animal data  used  for  subchronlc estimates  generally  reflect
exposure  durations of  30-90  days.   The  general  methodology  for  estimating
subchronlc RfDs  Is the  same as  traditionally employed for  chronic  estimates,
except that subchronlc data  are utilized when available.

    In  the case  of suspected  carcinogens, a carcinogenic potency  factor,  or
q-j*  (U.S.  EPA,  1980),  Is  provided.  These potency  estimates are  derived
for both  oral and  Inhalation  exposures   where  possible.   In addition, unit
risk estimates for  air  and  drinking water are presented  based  on  inhalation
and oral data, respectively.  An  RfD may  also  be derived  for the noncardno-
genlc health effects of compounds that  are also carcinogenic.

    Reportable   quantities   (RQs)  based   on   both  chronic   toxldty  and
carcinogenic!ty are derived.  The RQ Is  used  to determine  the  quantity of  a
hazardous  substance  for  which  notification Is  required  In  the event of  a
release  as   specified   under   the  Comprehensive   Environmental   Response,
Compensation  and Liability  Act  (CERCLA).   These  two RQs  (chronic  toxldty
and cardnogenlclty)  represent  two  of six  scores developed  (the  remaining
four reflect  1gn1tab1lHy, reactivity, aquatic  toxldty,  and acute mammalian
toxldty).   Chemical-specific  RQs reflect  the lowest of  these six  primary
criteria.   The  methodology  for  chronic   toxIcUy  and cancer  based RQs are
defined In U.S. EPA, 1984a and  1986a, respectively.
Ill

-------
                               EXECUTIVE  SUMMARY

    Pure  hydrazlne  1s a  colorless,  fuming liquid  with  an ammoniaca1  odor.
It  1s mlsdble  with  water and  soluble  In other  polar  solvents.  In  basic
solutions,  hydrazlne  acts as  a  strong  reducing agent  {Schlessl,   1980}.
Hydrazlne  Is  mainly produced In  the  United States by some variation  of  the
Raschlg process,  which 1s  based  on the  oxidation of ammonia with alkaline
       i
hypochlorlte  at  elevated   temperature and  pressure {Schlessl, 1980).    As  of
January 1989, only  Olln  Corp.  1n Lake Charles,  LA, produced  hydrazlne (SRI,
1989).  The  U.S. production volume  of   hydrazlne  was at least  16.6 million
pounds  In 1977  and 20 million  pounds (In  1982 {Schlessl,  1980; U.S.  EPA,
1984b).   Hydrazlne  production  grew at an  annual rate of 8-10%  through 1987
(U.S.  EPA.  1984b).   The  major  uses of  hydrazlne  are In the manufacture  of
agricultural  chemicals  (40%).  for  making  blowing agents  used   In polymers
(33%), as water  treatment chemicals  (15%), 1n aerospace  Industry as missile
fuel  (5%)  and In miscellaneous other  Industries (7%) (Schlessl,  1980; U.S.
EPA. 1984b).
    Under  most  conditions, reaction  with  ozone will be  the major fate  of
hydrazlne In  the atmosphere.  The half-life of  hydrazlne was  estimated to be
<10 minutes during  ozone  polllutlon episodes  and <2  hours  In natural  tropo-
sphere.   The  major  product of  the  reaction with ozone  Is  hydrogen peroxide
(Tuazon et a!., 1981).
    The estimated half-life of  hydrazlne 1n most natural waters  is 5-7 days
(MacNaughton  et  al..  1979,   1981).   The  oxidation  of  hydrazlne  In  the
presence  of  catalysts such as  metal  Ions  1s  probably  the most  significant
process for Us  loss  In  water  (Gormley  and Ford,  1973;  Slonlm and 61sclard,
1976).  At low concentrations, blodegradatlon may  be  responsible for  partial
                                      1v

-------
 removal  of hydrazlne  from water.  Volatilization may  remove  some hydrazlne
 from  water (Stauffer,  1977;  MacNaughton,  1979;  MacNaughton et  al.,  1981).
 Hydrazlne  may have  a  low to moderate  8CF  In aquatic  organisms  (Slonlm and
 Glsclard,  1976).
    According  to  Ou  (1987),  hydrazlne applied to a soil at concentrations of
 100 and  500 ppm  disappeared  completely In <1 and 8  days,  respectively, and
 btodegradatlon  was  responsible  for  -20% of  Its  disappearance  (Ou,  1987).
 Indirect evidence suggests that  chemical oxidation may  be  Important  for the
 loss  of  hydrazlne from  soil  (U.S.  EPA, 1984b).   Some  evaporation from soil
 surfaces   Is  expected  (MacNaughton  et  al.,  1981).    Hydrazlne   will  leach
 faster  1n  sandy  soils  than  from soils containing higher  amounts  of  organic
 carbon and clay (HSDB. 1989).
    Pertinent  monitoring  data  regarding  the  exposure of  Individuals  to
 hydrazlne  from  Inhalation  or  dermal routes  were not  located In the available
 literature  cited   In  Appendix A.   It  has  been  estimated  that  the  Finnish
 population  Is  exposed  to hydrazlne derivatives  from  the consumption  of
 natural  plant  Ingredients at  a  rate  of  -1 pg/day  (Hemmlnkl and  Vlanlo,
 1984).
    The  acute  toxlclty   of   hydrazlne  was   examined   reasonably well  In
 freshwater  fish.   Nevertheless,   data regarding  the  toxlclty  to  freshwater
 Invertebrates  or   salt  water  fauna  are  Insufficient,   precluding criterion
development.  The available  studies,  however, Indicate  trends  1n  the  toxlc-
 Uy of hydrazlne  to  freshwater fauna, including  fish,  toads, salamanders and
crustaceans.  Toxlclty  to the guppy  (Slonlm, 1977)  and salamander  (Slonlm,
 1986)  was  Influenced by water hardness,  with lower  LC5Qs  resulting  In soft
water.   Similarly,  Hunt  et   al.   (1981)  noted  an  Increase  In  hydrazlne
toxlclty  1n  bluegllls  at 24  hours  corresponding  to  an  Increase 1n  water
temperature.

-------
     For  bluegllls,  catfish  and  shiners,  96-hour  LC50  levels were  1.0-1.6
 mg/i (Hunt et  al..  1981; Fisher et  al.,  1980a,b,  1978).  Results  from  the
 Slonlm  (1977)  experiments  with hard  and  soft  water  yielded 96-hour  LC5 s
 of  3.85  and  0.61  mg/i,  respectively,  for  the  guppy.   The  rainbow  trout,
 however,  appeared  more  tolerant,   with  a  reported  76-hour  LC...  of  6.0
 mg/a   (Hu   and  Nakatanl,  1964).    Similarly,  Applegate   et   al.  (1957)
 reported  no  effects  In  larval  sea   lampreys  exposed  to 5.0  mg/i for  24
 hours.
     Other  effects  were  observed  In  freshwater  fish.   Southgate  (1950)
 observed  a  loss  of  equilibrium  In   trout  flngerllngs   at  0.7  mg/t  at  24
 hours,  and Fisher  et  al.  (1978)  reported  a  loss  of  balance  In  bluegllls
 exposed   to  hydrazlne  at  concentrations  as   low  as   0.0010  mg/i  for   30
 minutes.
    The  LC5Q  for  freshwater   toad  tadpoles  was   0.01  mg/i  for 120  hours
 (Greenhouse,  1976).   However,  the LC5Qs for  salamander  larvae were 8.0  and
 5.3  mg/i  In  hard water  and  5.2 and  2.3  mg/i  In  soft water  at 48 and  96
 hours, respectively  (Slonlm, 1986).
    Freshwater  algae were also tested with  hydrazlne.   S.  capMcornutum  had
 the   lowest   EC5_   (0.006  yi/i   for   3   days)   for   algal   growth   under
eutrophlc  conditions;  however,  a concentration  of  0.001  yi/i  for  3  days
was  Indicated as  safe  for  ollgotrophlc,  Intermediate  and eutrophlc  water
conditions (Harrah, 1977).
    The  saltwater  alga,  D.  tertlolecta.  was  exposed   to hydrazlne  under
similar  conditions   (Harrah.   1977).    Ollgotrophlc   conditions  yielded  a
slightly   lower   6-day   EC5Q   (0.0008   yi/i)   than  estuarlan  conditions
(0.0011  jii/i).    Brown   algae   (phaeophytes),   sporophyte  and  gametophyte
growth  and  viability  were  affected  at  hydrazlne  levels  as  low as  0.025
mg/i (James et al., 1987).
                                      v1

-------
    One  saltwater  fish, the  stickleback,  Gasterosteus  aculeatus.  was tested
with  hydrazlne  (Harrah,  1977).   The  96-hour  LC5Q  was  3.4 mg/i,  similar
to  freshwater  fish  IC5Q values.   However,  the  author  suggested  that  the
actual LCcg was probably lower because of degradation.
    Hydrazlne  appears  to be  absorbed extensively by  the  respiratory tract;
similar  doses administered  to rats  by  Inhalation or  Intravenous Injection
resulted  1n equivalent  urinary  excretion  values  (Llewellyn et  al., 1986).
Blood levels  of hydrazlne Increased  for  60-120  minutes 1n  rats after Inhala-
tion  exposure; however,  the  correlation  between atmospheric  concentration
and  blood  levels was  weak  (Dost et  al.,  1981).   Hydrazlne  was  detected In
the plasma  of dogs  within 30  seconds  of  dermal  application, Indicating that
hydrazlne  1s  rapidly  absorbed   by   this   route  (Smith  and  Clark,  1972).
Similar  to  the Inhalation exposures  reported  by  Dost  et  al. (1981), plasma
concentration  and  the  dermally  applied dose  were weakly  correlated (Smith
and Clark,  1972).  Hydrazlne  was  also rapidly  absorbed after dermal applica-
tion  to  rabbits;  the  total  percentage of absorption  1n rabbits  was  87X for
anhydrous hydrazlne, and 55X  for  70% aqueous hydrazlne (Keller et al., 1984).
    Tissue  distribution  of  hydrazlne  after  Intraperltoneal  and  subcutaneous
Injection was  rapid  In rats  and  mice (Nelson and Gordon,  1982;  Dambrauskas
and Cornish,  1964;  Kaneo  et  al.,  1984).   Peak  tissue levels were  reached
within 0.5-2 hours.  The highest  levels  were found  In the  kidney, spleen and
lungs; the  lowest levels were found  In the brain,  muscle and fat (Nelson and
Gordon, 1982;  Dambrauskas and Cornish, 1964; Kaneo et  al.,  1984).  The rate
of  distribution can  be estimated  from  the L ._   (0.74  hours)  calculated
                                               I / £
-------
 urine  (Springer et  al.,  1981; Nelson  and  Gordon,  1982).  Small amounts  of
 the  N-acetylated metabolites,  acetyl-  and  dlacetyhydrazlne,  have also  been
 Identified  In  urine.   Nelson  and  Gordon  (1982)  reported  that  25% of  an
 Injected  dose  of  hydrazlne  Is  converted to  acid labile conjugates.   HcKennls
 et  al.  (1959)  reported that  rabbits  excrete primarily  unchanged  hydrazlne
 and  smaller  amounts of mono-  and  dl-N-acetylated derivatives;  however,  dogs
 do  not excrete dlacetylhydrazlne.   Less  than  1%  of an  Injected   dose  of
 hydrazlne was  excreted Into bile  (Springer  et al.,  1981), and  no  hydrazlne
 was found In saliva or vomltus (HcKennls et al., 1955).
    Hydrazlne  lethality was dose-related  In  female mice exposed by  Inhala-
 tion continuously  to  0.26  or  1.3 mg/m9,  or  Intermittently  to  1.3 or  6.5
 mg/m3,  for  6  months;  the  percentages  of  mortality  were 2.5,  7.5,  35  and
 55X, respectively  (Haun and  Klnkead,  1973).   HepatotoxIcHy  may have  been
 the cause of  death.   Cornstock et  al. (1954)  reported high  levels of  mortal-
 ity  In  rats,  mice,  guinea pigs and  dogs  exposed to  18 mg/m3 for  <6  months.
 Jacobson  et  al.  (1955)  reported 4-hour  Inhalation  LCgQ  values  for  mice
 (330 mg/m3)  and rats (747 mg/m'}.
    The carcinogenic  potential  of  hydrazlne  was  assessed  In  an  extensive
 study of  Inhalation exposure  using  F344 male  and  female rats,  male Syrian
 Golden hamsters, male  and  female  C578B1/6  mice, and  male and  female beagle
 dogs (Carter et  al.,  1981;  NacEwen et  al., 1981; Vernot  et al.,  1985).   The
animals were exposed to hydrazlne  vapor at  concentrations of 0.07,  0.33, 1.3
and  6.5  mg/m*  for  rats and  hamsters,  0.07,  0.33  and  1.3  mg/m9 for  mice,
and  0.33  and  1.3 mg/m9  for   dogs over  a  12-month  period.   At 6.5 mg/m9,
 the  Incidence  of nasal benign (adenomatous polyps)  and  malignant  (squamous
cell carcinoma)  tumors  Increased  In  rats, and  the  Incidence of  nasal polyps

-------
and  thyroid  adenocarcinemas Increased  In  hamsters.   A significant  Increase
In  pulmonary  adenomas  was observed  1n  mice  exposed  to  1.3  mg/m».    No
carcinogenic effect was found In the dogs.
    Oral  exposure  to hydrazlne  Increased  the  Incidence of pulmonary  tumors
In  different strains  of mice   (IARC,  1973;  81andf1or1,  1969,  1970b,c,d,
1971;  Blanclflorl   and  Severl,   1966;   Blanclflorl  and  R1bacch1,  1962a,b;
Blandflorl  et  al.,  1963a,b,  1964;  Mllla, 1965;  Roe et  al.,  1967; Toth,
1969, 1971;  Kelly et al., 1969;  Yamamoto and Welsburger, 1970;  Bhlde et al.,
1976).   Mice  generally  developed  multiple  adenomas  and  adenocarcinemas.
Three  strains  of  mice  also developed  hepatomas  and hepatocardnomas  (IARC,
1973).   In contrast,  a decreased  incidence of  mammary gland  adenomas  was
observed  1n  female  C3H mice that  received  0.65 mg hydrazlne  dally 1n the
drinking  water  (Toth,  1969).   Blandflorl  (1970c)  administered  hydrazlne
sulfate  by gavage  to  8-ueek-old CBA/Cb/Se mice at  doses  of  0. 0.14, 0.28,
0.56  or  1.13 mg/day.   A  dose-related  Increase  In vasculartzed  hepatocard-
nomas was  observed  1n  both sexes.   Lung metastases were  also  found at the
highest dose tested.
    Severl and  B1andf1or1   (1968)  reported that  lung  tumors  (adenomas and
adenocardnomas) were  found  In  3/14 male and 5/18 female Cb/Se  rats exposed
from  the age of 8  weeks for 68 weeks to dally oral  hydrazlne doses  of 18  mg
for males  and  12  mg for  females.   Hepatic carcinomas  were also observed  In
4/13 males and  In  0/18 females.   No spontaneous hepatic carcinomas  had been
observed  previously  In  the Cb  rat colony  maintained In  this  laboratory.
Stelnhoff  and Mohr  (1988) concluded that hydrazlne was a weak carcinogen  In
Wlstar rats  that  received  0,  2, 10 or  50 mg  hydraz1ne/t until  spontaneous
death.   Benign  liver  cell   tumors were  observed  only at the highest concen-
tration tested.
                                      1x

-------
     Significant  Increases  In tumor Incidence were  not  found In two  studies
 of  Syrian Golden  hamsters   that  received  2.3 mg/day  1n  drinking water  for
 life   (Toth,  19725)  or  gavage  dos'es  of  2.8-3.0   mg/day  for  15-20  weeks
 (B1andf1or1,  1970c).   Bosan et  al.  (1987),  however, reported  an  Increased
 Incidence  of  hepatocellular  carcinomas  1n  Syrian  Golden  hamsters  that
 received 4.6, 8.3 or 10.3 mg hydraz1ne/kg/day for 2 years.
    Subcutaneous   injection  or   Intratracheal   Instillation   of  0.25-5  mg
 hydraz1ne/kg once/week  for  2.5 years  had  no  carcinogenic effect  In  male or
 female Sprague-Oawley rats (Stelnhoff and Nohr,  1988).
    Hydrazlne  1s  genotoxic  In  prokaryotes,  lower  eukaryotes,  Insects  and
mammals.  Hydrazlne caused DNA damage  In phage and  E_.  coll  (Helnemann, 1971;
Von  Wright,  1981;  Green, 1981)  and  In animal cells  In  vitro (Slna  et  al.,
1983), as  well  as  unscheduled  DNA synthesis  1n human Hbroblasts and  HeLa
cells  In vitro  (Agrelo and Amos,  1981; Nartln  and NcDermld,  1981).   Gene
mutations  were  observed  In  Salmonella (Wade  et  al.,   1981;  Anderson  and
Styles,  1978;  Herbold  and  Buselmaler,  1976;  Rowland  and Severn, 1981),  £.
coll  and  yeasts  (Noda et  al.,  1986;  Von  Wright,  1981;  Lemontt,  1978;
NcOougall  and  Lemontt,  1979).    Hydrazlne  Induced  somatic  mutations  In
DrosophUa (Shukla, 1972; Vljaykumar  and Jain,  1979) and mouse  L5178Y cells
in vitro (Rogers and Back,  1981).  No  effect of hydrazlne was observed In
tne  IE  vivo  mlcronucleus   test  or  the  dominant  lethal   assay  In  mice
(Tsuchlmoto and Hatter,  1981; Epstein et al.,  1972).
    Hydraz1ne-1nduced   systemic   toxldty  after   Inhalation   exposure   Is
observed  primarily In  the  liver, lungs  and blood.   Dogs  exposed   to  6.6
mg/m*  Intermittently  or  1.3  mg/m*  continuously  for   6  months  suffered
decreased  red  blood cell counts,  hemoglobin concentration and  hematocrUs.

-------
and  Increased  erythrocyte  fragility  (Haun and  Klnkead,  1973).   Under  the
same exposure  protocol,  fatty liver changes In mice and moderate fat accumu-
lation  In  the  liver  of rhesus monkeys were observed.  Similarly, Cornstock et
al.  (1954)  found  fatty  liver  changes  In  beagle dogs  exposed  to  18  mg
hydraz1ne/m"  for  <6 months.   Comstock and Oberst  (1952)  reported emphysema
and  Interstitial  pneumonltls In rats  and emphysema and atelectasls  In dogs
exposed  to 6  mg  hydraz1ne/m» for  31  weeks.   Chronic  Inflammation,  atelec-
tasls  and  lymphold hyperplasla were  observed  In guinea pigs  exposed to 3-6
mg/m»  for  2  weeks followed  by  8  weeks  at 4-8 mg/m* (Heatherby  and  Yard,
1955).   In  the  same  study,  pathological  changes noted  In  mongrel  dogs
exposed  to 3-6 mg/m»  Included  central-zone fatty  degeneration  and necrosis
of  the  livers  and accumulation of bile  pigment.   Capillary damage  In  the
kidney and lung atelectasls were also observed (Heatherby and Yard, 1955).
    MacEwen et  al.  (1981)  reported  that hydrazlne exposure caused aspermato-
genesls  or hypospermatogenesls  In  Syrian  Golden hamsters.   MacEwen  et  al.
(1981) also found  that female mice  suffered lesions Including ovary atrophy,
salplngltls  and  endometrltls when  exposed  to   6.6  mg hydraz1ne/m»  for  1
year.
    Systemic toxldty after oral exposure to  hydrazlne Is  similar to Inhala-
tion  exposure.   B1anc1f1or1  (1970a)  administered  hydrazlne by gavage  to
Syrian Golden  hamsters  (2.8-3.0  mg/hamster for 15-20 weeks; assuming a body
weight  of  0.14 kg.  this  Is  equivalent  to -20  mg/kg)  and observed severe
liver lesions  Including  cirrhosis,  bile duct  proliferation,  pressure atrophy
and  hepatocyte degeneration.  In  contrast, male albino  rats that  received
between  15 and 25 mg  hydraz1ne/kg/day for 3  or  4 weeks  suffered  no patho-
logical  changes of  heart,   lung,  liver,  spleen, stomach,  small  Intestine,
kidney, adrenal, pancreas or testes (Heatherby and Yard, 1955).
                                      x1

-------
 Induced  somatic  mutations In Drosophlla tShukla, 1972; Vljaykumar and Jain,
 1979;  Jain  et al.,  1969)  and  mouse  L5178Y  cells \n vitro {Rogers and Back,
 1981).   No  effect  of  hydrazlne  was observed  In  the  Ui  vivo mUronucleus  test
 or  the dominant  lethal assay  In  mice (Tsuchlmoto and Hatter, 1981;  Epstein
 et al.,  1972).
    Hydrazlne  does not  appear to  be  teratogenlc,  although  H  1s  clearly
 embryo- and  fetotoxlc  at  levels associated  with maternal  toxlclty.   Lee and
 Aleyasslne  (1970)  Injected pregnant  rats with 8 mg  hydrazlne/kg/day  subcuta-
 neously  on  gestation days 11-21.   None of  the hydrazlne-treated rats  gave
 birth  to newborns  that   survived  the first  24 hours,  while newborns  from
 untreated control  rats  survived.   Keller et  al.  (1982)  determined that  the
 most  susceptible  prenatal  period   regarding   embryolethalUy  1n  rats   was
 gestation  days  7-9.   Lyng   et  al.   (1980)   administered   Intraperltoneal
 Injections  of  4,  12, 20,  30  or 40  mg  hydraz1ne/kg  and  found that  maternal
 toxUHy was also  Indicated  by reduced weight  gain  (at 12 and 20 mg/kg) and
maternal death (4/21 rats died 1n  the 40 mg/kg group).
    Hydrazlne  was   assigned  to  EPA  we1ght-of-ev1dence  group  82.   probable
 human  carcinogen,  on  the basis of positive  results In cancer studies using
 rats, mice and hamsters (MacEwen et  al., 1981;  Toth,  1982; Roe et al., 1967;
Toth, 1969;  Sever 1 and BlanclfloM,  1968; BlanclHorl, 1970b,c; Bosan et al.
 1987)   A slope  factor  (q^)  of  17  (mg/kg/day)~l  was  derived  for  Inhala-
 tion exposure from the Increased  Incidence of nasal  cavity adenoma/carcinoma
 1n  rats  In  the  Inhalation study by Mac E wen et  al. (1981).  A  q^* of  3.0
 (mg/kg/day)~l  was  derived for oral  exposure  from  the  Increased  Incidence
 of  hepatoma  In   mice  In  the  gavage  study   with  hydrazlne   sulfate  by
 Blanclflorl  (1970a).   Both   slope   factors  have   been   verified   and   are
available on IRIS  (U.S.  EPA,  1989).  A  cancer-based RQ  of  1 was  assigned
based on the data of MacEwen  et al.  (1981).
                                      xll

-------
    Data yere  Insufficient  for  the  derivation  of  RfOs  for  subchronlc  and
chronic Inhalation and oral  exposures  to  hydrazlne.   An  RQ of 10 for chronic
(noncancer)  toxlclty  was   based   on   Increased  mortality   In  mice  1n  the
Inhalation  study by Haun and Klnkead (1973).

-------
                           TABLE OF CONTENTS  (cont.)

 6.   EFFECTS	6-1
      6.1.   SYSTEMIC TOXICITY	6-1
            6.1.1.   Inhalation Exposure 	  6-1
            6.1.2.   Oral Exposure	6-4
            6.1.3.   Other Relevant Information	6-6
     6.2.   CARCINOGENICITY	6-8
            6.2.1.   Inhalation Exposure 	  6-8
            6.2.2.   Oral Exposure	6-9
            6.2.3.   Other Relevant Information	6-24
     6.3.   GENOTOXICITY	6-25
     6.4.   DEVELOPMENTAL TOXICITY  	  6-31
     6.5.   OTHER REPRODUCTIVE EFFECTS 	  6-33
     6.6.   SUMMARY	6-34
 7.  EXISTING GUIDELINES AND STANDARDS 	  7-1
     7.1.   HUMAN	7-1
     7.2.   AQUATIC	7-1
 8.  RISK ASSESSMENT	8-1
     8.1.   CARCINOGENICITY	8-1
            8.1.1.   Inhalation	8-1
            8.1.2.   Oral	8-1
            8.1.3.   Other Routes	8-2
            8.1.4.   Weight of Evidence	8-2
            8.1.5.   Quantitative Risk Estimates 	  8-3
     8.2.   SYSTEMIC TOXICITY	8-4
            8.2.1.   Inhalation Exposure . 	  8-4
            8.2.2.   Oral Exposure	8-6
 9.  REPORTABLE QUANTITIES 	  9-1
     9.1.   BASED ON SYSTEHIC TOXICITY 	  9-1
     9.2.   BASED ON CARCINOGENICITY	.•	9-1
10.  REFERENCES	10-1
APPENDIX A: LITERATURE SEARCHED	A-l
APPENDIX 8: SUMMARY TABLE FOR HYDRAZINE	B-l
APPENDIX C: DOSE/DURATION RESPONSE GRAPHS FOR EXPOSURE TO HYDRAZINE.  .  C-l
                                      xv

-------
LIST OF TABLES

   Title
No.                               Title                                Page

1-1     Physical Properties of Hydrazlne, Hydrazlne Hydrate and
        Hydrazlne Sulfate  	  1-3

4-1     Acute ToxIcHy of Hydrazlne to Fauna	4-2

6-1     Incidence of Tumors In Mice, Hamsters and Dogs Exposed by
        Inhalation to Hydrazlne 	  6-10

6-2     Incidence of Tumors In Swiss Mice Treated with >95X
        Hydrazlne In Drinking Mater for 110 Weeks 	  6-13

6-3     Incidence of Lung Tumors In Female Swiss Mice Treated by
        Gavage with Hydrazlne 1n Distilled Water for 40 Weeks
        and Observed for 60 Weeks	6-14

6-4     Incidence of Tumors In Mice After Oral Exposure with
        Hydrazlne Sulfate (Certified ACS) 1n Drinking Water for Life.  6-15

6-5     Incidence of Tumors 1n Mice and Rats Treated by Gavage
        with Hydrazlne Sulfate 1n Water 	  6-17

6-6     Incidence of Tumors 1n Female BALB/c Mice Treated by
        Gavage with Hydrazlne Sulfate 1n Water for 150 Days 	  6-19

6-7     Incidence of Liver Carcinoma 1n CBA/Cb/Se Mice Treated by
        Gavage with Hydrazlne Sulfate 1n Water for 25 Weeks,
        6 Days/Week	6-20

6-8     Incidence of Hepatocellular Carcinomas 1n Livers of Male
        Syrian Golden Hamsters Treated with Hydrazlne Sulfate
        (<95X) In Drinking Water for 2 Years	6-21

6-9     Genotoxldty Testing of Hydrazlne	6-28

9-1     Hydrazlne: Minimum Effective Dose (MED) and Reportable
        Quantity (RQ)	9-2

9-2     Derivation of Potency Factor (F) for Hydrazlne	9-4
      xv1

-------
                               LIST OF TABLES

No.                               Title

3-1     Estimated Dally Dietary Intake of 1,2-Dlbromoethane by
        Geographical Region of the United States	3-3

6-1     Incidence of Tumors 1n F344 Rats and B6C3F1 Mice Exposed
        by Inhalation to 1,2-Dlbromoethane	6-13

6-2     Incidence of Tumors 1n Sprague-Dawley Rats Exposed by
        Inhalation to 1,2-Dlbromoethane Vapor for 18 Months 	  6-1?

6-3     Incidence of Tumors In Osborne-Mendel Rats and B6C3F1
        Mice Treated by Gavage with 1,2-Dlbromoethane 	  6-20

6-4     Incidence of Tumors of the Forestomach In Male and
        Female B6C3F1 Mice Exposed to 1,2-Dlbromoethane 1n the
        Drinking Water	6-22

6-5     Genotoxlclty Testing of 1,2-Dlbromoethane 	  6-25

9-1     1,2-Dlbromoethane: Minimum Effective Dose (MED) and
        Reportable Quantity (RQ)	9-2

9-2     Derivation of Potency Factor (F) for 1,2-Olbromoethane. . .  .  9-5
                                     xv1


-------
                             LIST OF ABBREVIATIONS
 AEL      Adverse effect level
 8CF      Bloconcentratlon factor
 BSP      Bromosulfophthaleln
 CAS      Chemical  Abstract  Service
 CNS      Central  nervous  system
 CS        Composite score
 ONA      DeoxyrlbonucleU add
          Concentration  effective to 50% of recipients
          Effective dose to  50%  of recipients
 EDTA      Ethylenedlamlne  tetraacetlc acid
 PEL       Frank effect level
«5T       Gene mutation, mouse L5178Y cells in vitro. TK locus
 HEC       Highest effective  concentration
 HID       Highest Ineffective dose
 Kow       Octanol/uater  partition coefficient
 LC§o      Concentration  lethal to 50% of recipients
          (and all other subscripted dose levels)
 LOH       Lactate dehydrogenase
LOU       Log dose unit
LED       Lowest effective dose
MED      Mixed function oxldase system
NOEL     No-observed-effect level
PEL      Permlssable exposure level
pKa      Negative log^o of dissociation constant
ppm      Parts per million
                                     xv11

-------
RfD
RNA
RQ
RVd
RVe
SAMM
SC
SCE
STEL
TLV
TWA
v/v
w/v
 LIST OF ABBREVIATIONS  (cont.)
Reference close
R1bonuc1e1c add
Reportable quantity
Dose-rating value
Effect-rating value
Standard algal assay medium
Safe concentration
Sister chromatld exchange
Short-term exposure level
Threshold limit value
Time-weighted average
Volume per volume
Height per volume
                                     xvlM

-------
                               1.  INTRODUCTION
 1.1.    STRUCTURE AND CAS NUMBER
     Hydrazlne  Is also  known by the synonyms dlamlne,  anhydrous hydrazlne and
 hydrazlne  base (Chemllne,  1989).  The chemical structure, molecular formula,
 molecular  weight and CAS Registry  number of hydrazlne are as follows:
 Molecular  formula:  H.N_
 Molecular  weight:  32.05
 CAS  Registry Number:  302-01-2
 1.2.    PHYSICAL AND CHEMICAL PROPERTIES
     Pure  hydrazlne  Is  a colorless, mobile, fuming  liquid with  an ammoniaca1
 odor.   It  Is mlsdble with  water  and soluble  In other polar solvents such as
 ethanol,  but  1s  slightly soluble  to almost Insoluble  In  less  polar  and non-
 polar  solvents,  such  as halogenated hydrocarbons and hydrocarbons (Schlessl,
 1980;  IARC,  1973).   Hydrazlne   Is  a  basic   compound wHh  a  nucleophlllc
 character,  and  a pKa value  of  7.93 at  25°C.   It reacts  with  HC1,  HBr,  HI,
 HN03,   HC104,   H2S04  and  other  Inorganic  and   organic  adds  to   yield
 salts.   It can  act  as  both an  oxidizing and  a  reducing  agent.   In  basic
 solutions,  hydrazlne  Is  a  strong reducing  agent  but Is  much  less  so  In
 acidic  media.   The reduction  of  hydrazlne  to  ammonia Is  thermodynamlcally
 favored  In add solution;  however,  the rate  of this reaction  Is generally
 slow  (Schlessl,  1980).   Hydrazlne  reacts  violently  with  metal oxides  and
 oxidizing  agents  (IARC, 1973).    It  decomposes  Into nitrogen and ammonia  at
 ~350°C  and Into nitrogen and hydrogen  at  higher temperatures  (Yaws et  al.,
 1974).


0322d                               1-1                               01/19/90

-------
     Selected  physical  properties of  hydrazlne and  hydrazlne  sulfate (repre-
 sentative of  Its  salts) are given In Table 1-1.
 1.3.    PRODUCTION DATA
     In  the  United States, hydrazlne  Is produced  mainly  by some variation of
 the  Raschlg  process,  which  1s based  on  the  oxidation of  ammonia  with
 alkaline hypochlorlte  at  elevated temperature and pressure (Schlessl, 1980).
 Fractional  distillation  of the  reaction product  produces  hydrazlne hydrate.
 Anhydrous hydrazlne  Is obtained by azeotroplc distillation  of  the hydrate,
 usually In  the presence of aniline.
    As  of  January,   1989,  only  Ol1n  Corp.,  Lake  Charles,  LA,  produced
 hydrazlne,  and  the  following  companies  produced the  hydrate In  the United
 States  (SRI.  1989):
         Bayer USA Inc., Baytown, TX
         Falrmount Chemical Co.. Inc., Newark, NJ
         Hummel Chemical Co., Inc., South Plalnfleld, NJ
The U.S. production  volume of hydrazlne was  at  least  16.6 million pounds In
 1977 (Schlessl, 1980) and  20  million  pounds  1n 1982. a decrease of -40% from
 the  previous  year  because  of   the  economic   recession  1n vital  Industries
 (U.S.  EPA,  1984b).   It  was  estimated  that,  excluding  production  for  fuel
 use. 21.6 million pounds  of  hydrazlne  was produced In  the United States in
 1984,  -1  million pounds  of  the chemical  was Imported and 3 million pounds
was  exported  during  the  same   year  (HSDB,   1989).   The  current  production
 volume  of   hydrazlne  Is  not available,  but   1t grew at an estimated annual
 rate of 8-10% through 1987 (U.S. EPA, 19845).
 1.4.   USE  DATA
    The major uses of  hydrazlne are  in agricultural  chemicals mostly 1n the
manufacture of pesticides  (40%), for making  blowing agents used 1n polymers
0322d
1-2
03/27/90

-------
                                   TABLE  1-1
  Physical Properties of Hydrazlne, Hydrazlne Hydrate and Hydrazlne Sulfate3
Property
CAS number
Chemical formula
Molecular weight
Physical statec
Melting point, °C
Boiling point, °C
Flash point, °C
(open cup)
Density at 25°C (g/ml)
Vapor pressure (mm Hg)
Odor threshold6
air, ppm (v/v)
water ppm (w/v)
Water so1ub111tyc (mg/i)
Logf Kow
Hydrazlne
302-01-2
N2H4
32.05
colorless
liquid
2.0
113.5
52.0
1.0045
14.4
3.7
160
mlsclble
-2.07
Hydrazlne
Hydrate
7803-57-8
N2H4.H20
50.06
colorless
liquid
-51.7
120.5
72.0
1.03 at 21°Cd
NR
NR
NR
mlsdble
NR
Hydrazlne
Sulfate0
10034-93-2
N2H4»H2S04
130.12
colorless
liquid
254
decomposes
NR
1.37
NR
NR
NR
34,150,000
NR
 Source: ScMessl, 1980 (unless otherwise specified)
 These values were obtained from Weast, 1985.
cThe  physical  states  and the  water  solubility of  the  first  three  compounds
 were  obtained  from Ueast  (1985)  and  the  last  two compounds  from Ulndholz
 (1983).
 This value was obtained from Ueast. 1985.
 These values were obtained from Amoore and Hautala, 1983.
 These values were obtained from Hansch and Leo,  1985.
NR - Not reported
0322d
1-3
03/27/90

-------
 (33%),  as  water  treatment  chemicals  (15%), In  the  aerospace Industry as a
 missile  fuel  (5%) and  In   miscellaneous  other  uses  Including use as a  fuel
 cell  In  the  F-16 combat fighter, as a  chelatlng agent and  In making  pharma-
 ceutical*, dyes  and explosives  (7%)  (U.S. EPA,  1984b;  MacNaughton et  al.,
 1981;  Schlessl,   1980).   Approximately  80% of   hydrazlnes  are  used  In  the
 synthesis of  agricultural  chemicals,  chemical blowing  agents, pharmaceutical
 Intermediates and  other  uses.   Generally, the only uses  for  which  hydrazlne
 1s  sold  as  a primary  product  are for water treatment chemicals  and  propel-
 lents for rockets and the F-16 jet (U.S. EPA,  1984b).
 l.S.   SUMMARY
    Pure hydrazlne  Is  a  colorless,  fuming liquid with  an ammonlacal  odor.
 It  Is mlsdble  with  water and  soluble 1n other  polar  solvents.  In  basic
 solutions,   hydrazlne  acts  as  a  strong  reducing agent  (Schlessl,  1980).
Hydrazlne Is  mainly produced  In  the  United States by some variation  of  the
Raschlg  process,  which  Is  based on the  oxidation of ammonia with  alkaline
hypochlorlte  at  elevated temperature and pressure (Schlessl, 1980).   As  of
January  1989, only  OUn Corp.  In Lake  Charles,  LA,  produced  hydrazlne (SRI,
1989).   The  U.S. production volume  of  hydrazlne  was  at least  16.6  million
pounds  In  1977  and 20  million  pounds   In 1982 (Schlessl,  1980; U.S.  EPA,
1984b).  Hydrazlne  production  grew at  an annual rate of 8-10%  through 1987
 (U.S. EPA,  1984b).  The  major  uses of hydrazlne  are  In the  manufacture  of
agricultural   chemicals   (40%),  for making blowing agents  used   In  polymers
 (33%), as water  treatment  chemicals  (15%), in aerospace  Industry as  missile
fuel  (5%) and 1n miscellaneous  other  industries (7%) (Schlessl, 1980;  U.S.
EPA, 1984b).
0322d
1-4
01/19/90

-------
                      2.   ENVIRONMENTAL  FATE AND TRANSPORT
 2.1.    AIR
    The vapor pressures  of  hydrazlne (see Table  1-1)  suggests  that It will
 exist  predominantly 1n the vapor phase 1n the atmosphere (E1senre1ch et al.,
 1981).
    The estimated  half-life of  hydrazlne  In the  atmosphere,  based  on Us
 gas-phase  reaction  with  oxygen,  1s  1-10 hours  (MacNaughton et  al..   1979,
 1981).   Investigations of the chemistry of hydrazlne In the atmosphere  using
 fluorocarbon-fllm environmental chambers, such as  those used by HacNaughton
 et  al.  (1979,   1981),   may  have  overestimated  the  rate  constants  for
 homogeneous   oxidation reactions  with  CL  by  Ignoring the  adsorption  of
 hydrazlne  to  and  permeation  through the reaction  chamber wall (Stone et al.,
 1989).
    The rate  constant for the  gas-phase  reaction  of  hydrazlne  with hydroxyl
 radicals  was  determined   to be  6.1x10" cmVmolecule-sec  (Harris  et  al.,
 1979).   Using an average  hydroxyl  radical  concentration  of  10* radicals/
 cm9  for  the  lower  troposphere,  the   authors  estimated  the  tropospherlc
 half-life  for  hydrazlne,  based  on  this  reaction,  to be  ~3  hours.   In
 polluted  urban  atmospheres  containing  higher  concentrations  of  hydroxyl
 radicals and  1n  unpolluted rural atmospheres  containing lower concentrations
 of  hydroxyl  radicals, the  estimated  half-life of  hydrazlne  was  
-------
 concluded  that under  roost conditions,  reaction  with 0-  will  be the  major
 fate  of  hydrazlne 1n the atmosphere, and according  to Tuazon  et  al.  (1981),
 the major product of that reaction Is hydrogen peroxide.
 2.2.   WATER
    The  reaction  of  hydrazlne  and  oxygen  1n  water,  which   was  slow  and
complex, could  not  be represented  by a simple rate  constant  (Ellis  et al..
1960).   The  abiotic  reaction of  hydrazlne  with dissolved oxygen  in  aqueous
solution appears  to  be slow  In  the  absence  of catalysts.  The most effective
catalyst  seems  to  be  Cu  ,   although CO^,  Ag     and  Hg    can  catalyze
this  reaction.    The  oxidation   rate  depends  not  only  on 0?  concentration
but also on  pH.  The  reaction  proceeds rapidly only In  basic  solutions  and
almost stops 1n acidic solutions (Gormley and Ford, 1973).
    MacNaughton et al. (1981) summarized the results  of  experiments  In which
the  degradation  of  3.2  mg/t  added  hydrazlne  was  monitored  In  distilled
water, and waters from a pond and  sea.  The pH was  8.0  and  the  temperature
was 25°C.  The  loss  of hydrazlne In distilled water In 6 days  was too low to
be measured, but  "20 and  40% loss  occurred  In the pond and seawater,  respec-
tively.   The  loss   of  hydrazlne,  presumably  from  catalytic  oxidation  by
metals  (such as  copper), could not  be correlated  with chlorine  content.
Ionic strength or suspended materials In these waters.
    The  disappearance  of hydrazlne  In  several natural,   treated  and  labora-
tory  waters  was studied  by  Slonlm  and Glsclard  (1976),  who  determined that
hardness and  organic material content  are  more Important than the  tempera-
ture  and dissolved oxygen content of these  waters  in increasing  the  rate of
disappearance  of  hydrazlne.  When  5.0  mg/i hydrazlne  was  added to  waters
from  a   river  and a  lake,  no  hydrazlne was  detected  after 4 days.  In  a
treated  water  with  low  hardness,  only 10% of  hydrazlne disappeared 1n  4
0323d
2-2
03/27/90

-------
 days;  however,  the  authors  did  not provide  any  evidence  of  the  specific
 abiotic reactlon(s)  that  were responsible  for  the degradation of  hydrazlne
 and  the  effect  of  specific  variables  (e.g.,  catalytic  effect  of   Cu*2
 Instead of total  hardness)  In determining the  rate  of  reaction.
     The   reaction   of   hydrazlne   with   hydroxyl   radicals   In   water   1s
 pH-dependent,  and  the  reaction  Is  faster at higher pH.   At  a pH  of 10,  the
 rate constant for  this reaction Is  1.4xl010/M-sec  (Hayon and S1m1c, 1972).
 If the concentration of hydroxyl  radicals  In  eutrophlc waters Is assumed  to
 be 3x10" M (Mill  and  Mabey, 1985), the  half-life  for this  reaction can  be
 estimated  as  19  days.   Therefore,  for most natural waters  where  the  pH  Is
 <10,   the   reaction  of hydrazlne   with   photochemlcally   produced   hydroxyl
 radicals In water will  not  be significant.
     Pure  cultures  of  Azotobacter  v1ne!and11  are  capable  of  metabolizing
 hydrazlne.  Although  nitrogen  and ammonia   are   minor   products   of   this
 blodegradatlon/transformatlon process,  the  major metabolites have  not   been
 Identified  with   certainty  (Bach,  1957;  Olamantls  and  Roberts,  1960).
 According  to Ou  and  Street  (1987),  the  soil  bacterium,  Achroreobacter   sp.,
 also  degrades  hydrazlne  1n   water.  The  degradation  rate   decreased   from
 92-95%  to  50%, with  Initial  hydrazlne  concentrations  of  17-34  and 68 mg/l,
 respectively.   The  authors  concluded  that  slower  degradation  was due  to
 hydrazlne  toxlclty  to the bacterium  at higher Initial concentrations
    The  blodegradatlon  of  hydrazlne  by  four  cultures   of  microorganisms
 available  1n aquatic  environments  was studied  by Kane and Williamson (1983).
 At  Initial  concentrations of  50  ppm, hydrazlne was  degraded in 7 days by two
 nitrifying  bacteria,  NUosomonas  and   Nltrobacter.   and  an  unspecified
 denitrifying  bacteria,  In  the presence  of  typical  nutrients.   Degradation
0323d                               2-3                              03/27/90

-------
was  20% In  the  absence of  nutrients.   An  unspecified culture of  anaerobic
bacteria  also degraded hydrazlne.   Hydrazlne  was  degraded by  live  NUroso-
monas  as  a  cometabollc,  and the primary  degradation  product was N»  rather
^^——                                                                £
than  NH.,  NO-  or  NO-.    The   authors  also  observed  that  hydrazlne  was
toxic  to  the microorganisms at higher concentrations.  WHh  N1 trosoroonas  as
the  degrading  microorganisms,   the  toxic   concentration  defined   as  the
concentration  required  to reduce substrate  metabolism by 50%  was  estimated
to be 94.8 ppm.  The  slow degradation  and  the toxlclty at low concentrations
Indicate  that blodegradatlon may not  be significant  when large amounts  of
hydrazlne are released In water.
    With an  air  velocity  at the liquid surface of  0.64 m/sec,  the  volatili-
zation of hydrazlne from  aqueous  solutions was measured,  and  the  volatiliza-
tion rates were  found to  decrease  with  the decrease  In  the  aqueous concen-
tration  of  hydrazlne.    At  a  concentration  of  25%,  <5% of  the  original
hydrazlne evaporated  In 5  hours.   In addition,  the rate of  volatilization
decreased with  time,  probably  from hydratlon and  sorptlon  of CO.  from  air
(Stauffer, 1977; HacNaughton,  1979; NacNaughton  et al.,  1981).   Therefore,
the   volatilization   of    hydrazlne  may    be   significant   for   spills.
Volatilization may not   be  significant  for  hydrazlne   1n  diluted  aqueous
solutions because H 1s expected to  be found In most natural  waters.
    The bloconcentratlon  of hydrazlne In  gupples,   PoedHa  retlculata.  has
been studied  by Slonlm and  Glsclard (1976).   At an  Initial hydrazlne concen-
tration  of  0.5  mg/i  in  hard  water, which  contained  440 mg/i  of  CaCO^
in a static  system,  the wet weight  BCF  (ratio'of concentration in  fish over
concentration  In  water)  In whole  fish  was  288 after  96  hours.    In  soft
water,   which  contained  20 mg/t   of  CaC03.  and   at  an  Initial  hydrazlne
0323d
2-4
03/27/90

-------
 concentration  of  0.25  mg/i,   no  bloconcentratlon  In gupples  was  detect-
 able.   Therefore,  hydrazlne In hard water may have  low to  moderate blconcen-
 tratlon 1n fish.
     The  estimated  half-life  of  hydrazlne  In  most  natural  waters  (e.g.,
 ponds,  rivers  and  lakes)  are 5-7  days,  respectively  (HacNaughton et a!..
 1979,  1981).
 2.3.    SOIL
     There are  few  data on  the fate  of  hydrazlne  In  soil.   In experiments
 with  soils  containing  different  amounts  of  sand,  clay and  organic  carbon
 content,  hydrazlne  sorptlon was minimal  In  sandy  soils and maximal  In soils
 containing clay (HSDB,  1989).  The  Increase  of hydrazlne  sorptlon 1n soil
 containing clay 1s  related to Its cation exchange property.  The leaching of
 hydrazlne was high  In sandy soil  and low In soils containing organic  carbon
 and clay,  particularly at  higher pH  (HSOB,  1989).
    The  ability  of  Achromofaacter  sp.,  Isolated   from soil,  to  blodegrade
 hydrazlne was reported by Ou  (1987)  and  Ou and Street (1987).  The  Achromo-
 bacter  sp.  has  a  short lag time for growth and  degrades hydrazlne  at concen-
 trations  >100 ppm; however,  the  Inability  of Achromobacter sp.  to grow on
 hydrazlne as  a  sole source of  nitrogen  Indicates  that the metabolic process
 for hydrazlne 1s cometabollc.   The rapid  degradation of hydrazlne at concen-
 trations  >100  ppm  by Achromobacter  sp.  suggests  that degradation  of this
 compound  by soil  microorganisms  is  possible.   A Bacillus  sp.  and a Pseudo-
 monas  sp.  also  degraded  hydrazlne  at   concentrations  <25  ppm.   It  was
 reported  that hydrazlne applied  to  a soil at concentrations of 100 and 500
 ppm  completely  disappeared   In  <1  and  8  days,  respectively,  and  that
 blodegradatlon was  responsible for  ~20X of  the disappearance of the chemical
 (Ou, 1987).
0323d
2-5
03/27/90

-------
    Chemical  reactions,  particularly  oxidation,  will contribute to  the  loss
 of  hydrazlne  from soil.   The soil column experiments performed  to  study the
 leachabinty  of  hydrazlne  In  different  soils   (U.S.   EPA,  1984b)  provide
 Indirect  evidence  for   the  chemical  reactions.   In  the  case  of  spills,
 volatilization loss from  the surface  of  soil  may be significant (MacNaughton
 et  al.,  1981).   However,  the  loss of  hydrazlne through volatilization  may
 not  be  significant  at  low hydrazlne  concentrations,  and  this  loss  will
 become increasingly Insignificant as the soil depth Increases.
 2.4.   SUMMARY
    Under  most conditions,  reaction  with ozone will be the major  fate  of
 hydrazlne  in  the  atmosphere.  The  half-life  of hydrazlne was  estimated to be
 <10 minutes during  ozone  polllutlon episodes and <2  hours  In natural tropo-
 sphere.  The  major  product of the reaction  with ozone  Is  hydrogen peroxide
 (Tuazon et al.. 1981).
    The estimated half-life  of  hydrazlne In  most natural waters  Is 5-7 days
 (MacNaughton  et  al.,  1979,  1981).   The   oxidation  of  hydrazlne  In  the
presence of  catalysts such  as  metal  Ions Is probably  the most  significant
 process for Us  loss  In water  (Gormley and  Ford,  1973;  Slonlm and  Glsclard,
 1976).  At low concentrations, blodegradatlon may  be responsible  for partial
 removal of hydrazlne  from water.   Volatilization  may remove  some  hydrazlne
 from  water (Stauffer,  1977;  MacNaughton, 1979;  MacNaughton  et al..  1981).
Hydrazlne  may have a low to moderate BCF in aquatic organisms  (Slonlm and
Glsclard, 1976).
    According  to  Ou (1987)* hydrazlne applied to a  soil  at  concentrations of
 100 and  500  ppm  disappeared completely  1n <1 and  8  days,  respectively, and
blodegradatlon was  responsible  for  -20% of  Us disappearance  (Ou,  1987).
0323d
2-6
03/27/90

-------
 Indirect  evidence suggests that chemical  oxidation  may  be Important for  the
 loss  of  hydrazlne  from soil  (U.S.  EPA,  1984).   Some  evaporation from  soil
 surfaces   Is  expected  (MacNaughton  et   al.,  1981).   Hydrazlne  will   leach
 faster  In sandy  soils  than from soils  containing higher amounts of organic
 carbon  and clay  (HSDB,  1989).
0323d                               2-7                              03/27/90

-------

-------
                                  3.   EXPOSURE

     Human  exposure  to hydrazlnes Is expected to occur primarily from  Us use
 as  a boiler water treatment agent and as an  aerospace propellant.
 3.1.   WATER
     Hydrazlne  has  been  monitored  at  a concentration  of  0.01  mg/4  1n  an
 outflow  pipe  from  an  Industrial  facility 1n  Lackawanna,  NY  (U.S.  EPA,
 1984b).   Additional  monitoring data for hydrazlne  In water  were not  located
 1n  the available  literature cited In Appendix A.
 3.2.   FOOD
     It  has been estimated  that  the Finnish population  Is  exposed to hydra-
 zlne derivatives  from the consumption of natural  plant  Ingredients at a rate
 of  ~1 ng/day (Hemmlnkl  and Vlanlo,  1984).
 3.3.   INHALATION
     No monitoring data regarding the level  of  hydrazlne In air were  located
 In   the  available   literature   cited  Appendix  A.   Considering  the  short
 residence  time  of hydrazlne  In  air,  exposure  through  Inhalation  may not  be
 an  Important route.   The smoke  from  a  blended  U.S. cigarette contained 31.5
 ng  hydrazlne (HSDB,  1989).
 3.4.   DERMAL
     Pertinent monitoring data regarding  dermal exposure  to hydrazlnes  were
 not  located In the available literature cited 1n Appendix A.
 3.5.   SUMMARY
     Pertinent  monitoring  data  regarding  the' exposure  of  Individuals  to
 hydrazlne  from  Inhalation or  dermal routes  were not located In the available
 literature cited  In  Appendix  A.   It has  been estimated  that the Finnish pop-
 ulation  1s exposed  to hydrazlne derivatives from  the consumption  of natural
 plant Ingredients at a rate of -1 yg/day (Hemmlnkl and Vlanlo, 1984).
0324d                               3-1                              01/19/90

-------

-------
                          4.   ENVIRONMENTAL TOXICOLOGY
 4.1.   AQUATIC TOXICOLOGY
 4.1.7.   Acute   Toxic   Effects   on  Fauna.    Pertinent  data  regarding  the
 effects  of acute  exposure of aquatic  fauna to  hydrazlne  are summarized  in
 Table  4-1.   Investigators  reported mortality  and toxic effects  In several
 species of  freshwater  fish, amphibians and arthropods.
    Slonlm (1977)  studied   the   toxldty   of  hydrazlne  gupples,  Leblstes
 retlculatus.  exposed  In  hard  or  soft  water.    The  96-hour  LC     In  hard
 water   (400-500   mg  CaC03/l)  was  3.85  mg/l.  whereas  the  corresponding
 LC5Q    In   soft    water    (20-30   mg   CaC03/l)   was   only   0.61   mg/l.
 Similarly,  Hunt  et al.  (1981)  reported  Increasing  toxldty with  Increasing
 temperatures  1n  bluegllls, Lepomls macrochlrus.  exposed  to  hydrazlne for 24
 hours  under static conditions.  Test  temperatures of 10.  15.5  and  21'C had
 corresponding   LC5Qs   of   7.7,   3.8   and   1.7   mg/l,   respectively.    The
 relationship  had  effectively diminished  by 96  hours In  a continuous-flow
 test,  with  LC5Qs  of  1.0-1.6  mg/l.    Fisher   et al.   (1980a)  reported  a
 96-hour  (static)  LC5Q  1n  this  range   (1.08  mg/l)  with  L.  macrochlrus  at
 23-24°C  and a  continuous-flow NOEL  of 0.43 mg/t.   However, Fisher  et al.
 (1978) observed  a loss of balance  1n 1. macrochlrus  exposed to hydrazlne at
 0.0010-0.01 mg/l for as few as 30 minutes under static conditions.
    Experiments  with  rainbow trout.  Salmo  galrdnerl. resulted  In mortality
 within  22-35  minutes  of exposure  to  146 mg/l  (Cortl,  1950).   Flngerllngs
 exposed  to  0.7  mg/l  for   24  hours   experienced  a  loss  of  equilibrium
 (Southgate, 1950),  whereas L1u and  Nakatanl (1I964)  reported  a  76-hour  LC.Q
 of 6.0 mg/l under static  conditions.
    Fisher  et al.  (1980b) reported  static  96-hour  LC5C)s  of 1.00  and  1.12
 mg/l  for  the  channel  catfish,   Ieta1oras   punctatus.  and golden  shiner.
0325d                               4-1                              03/27/90

-------






















e
3
e
-—
«
e
»»

<*.
**

u
X
O
*
<*»
3
U
















w
V
01
01







c
I
1

v» O — •
c i» -s.
»_ X
«*> v» ^-«
"

Of
^ ^T
f



s


**
tt
u.
UJ

e v»
O t-
*- 3
*•* e
*,* |£y
e CF»
 e
4. • • tj> e <•
41 r— •••• f ^ **
e k a iifl 3 J<
01 x o O O» — H
Z 01 U l/> •— ^ K
.n «

1 3
CM 1*
rv o
o» &
k e x
x i tS ^>
l|||
* |EJo < <


g « «
— z z z
kO
1
r«— CO BC C^

in
.^
i >/>
° oc oc

e ti
*•• 1^ k
S S * i
*» ** fl* 13 •** k- **
*j g»> 5 5 'SS 5
fl) O in 3* *^ O *^ *^
k"S.5 i * M^ •<
2|^^ g S3- Q
«iool •- « I




< < « «
s s
•Q ^ U
oo o
-^5 S «?
-
2 5 2a S

1
e w
^ 2 **
§* s s 5
U «k Z Z  01 o 41
I7fcv, »i »i=^ »-^
lE-ii* J 31 JSISi Jo

V
^
m
e
e
trt


VI
VI

3 C
B «

?f
i =
s
i
§

Lf>
_
CM
CM
CM

(V)
CO
CD


SH

*"•
II



. in


^ .
i S
£ m

3
~
V
i
ss
VI —
S|
«w
**la
if

fw.
on
*""
|
5»



vt

_3 C
Ik k
*• f
«> .a
S ^

c^
1

y,
^
ry
i
CM
CM

O>
•^
1



«j
•»
58
gS



^
•0
O


in
-

S
—
3
^ ^
*v e
a
*a
**

b
1
*•* ^
^2



IV W

3 01 3
•— Q. O
•sl*
*- «** »
(*w
^•e "
X U k
e e 3
0
1
S



wo
•— vX O
CM r- r—

O
0
1



^^
*™
Su
=1




CMO «e



S

2"£
1
g .s
Ik *• O k t»
llll*
VI  en
!«•
z2 k
• J

e k a
•
VI — «•• B C
v^O, 2 S 0
3*-" »t?
•O M W J
* ** Z * *
!5li5 is I
CM
JC

o «•
CM i—

^

-S*Si



s

;
,
i
1 11
vt
a
|
K
0325d
4-2
01/19/90

-------
o
u







Hardness






|
central
e
o ^
0> *>t
II
Q.
at
e
1





u
e
17


^
"c

O — -
!« •»*
<9
01
Temperatui
pc)
a

1

9

w<
o
z
OB
VI
1
(M

1
^~
Ol
VI
V
1-
Ol O» t .2 "~ § "" 3
ifl * if • O
•§* •§§ fig ** f* *j£
£2 £1 £5 ft It £?
i_ •>. ME i Ol
01 T3 41 >• OlO -0 C i.
_2 ••-• •oo»-"*^o'~Sei.
~> ottn o > o «• o 3 i- —
iood* 5**'»w c 5 o "e ***-o
EXO-EOI ^ i. a o o i- u I1 v i
O-rt^c Sto'^^'— -^jooi-O
nu.ooo.az z z z waio— Siflfco-^Ai^e
IM CO
ffl 1 f—
IM 9 — f-
at >e o o o
fM ^ — vn -- z

» CM f\j
CM IM  •— CK
IM CM CM m eg z
i~ CD r^ « r^
t P 1 r 1
^» «^ tfl ^1 ^^
p*^ ^ft ^9 ^* ^^ ^E
•— Ol C S3
MS C O — »» B
U*O-*™ *" Wlfc. «""•
s r r g I!III ?^ rf
iq —m «m •> a, «i o> v •— 3 *•*<>
Ol S — ' Q — ' O O«iifl'OOOO(»>OO«J
^a I— i~ c It>.-^u «!-•- »I —

§ 2
5 ~ ~ 5 5 55
o e
vn — • ^"S
S< « < < • < i— c o
Z Z Z Z •-— Al~_ I
-S- '-
o -- •o i • o in
S 5 5 ,n dgi. 5 A.-5S
I
|
u u u u e w
^ 4-* ** ** +* 11 •*«
? 5 » H
^ '1 Cl VI ~~ C C 4> •!
£ — cam C _C i« »- O> -0^5
^S »-S2 *"53 *">ij~'Dv>SISS — ** £ 3
^m O*^^&-••- £iJ§^ *«S
     0325d
4-3
01/19/90

-------
5      VI ^^
      «
  e
  o
  IQ
  k


  1
  U
  e
  e
  I
5
      u
              k * CM l_   u

                   It-   X
             •O O ^ —   O
              o< •"•• o 3   »>

              0« O*   0.
             tti—
             X 3
               §
               ui
                I
               §
                                  CM
                                  CM
                      CM  CM
                      CM  CM
                                CM
                                I


                                CM
                                       « n> og>
                                       "~ fek?

                                       vi   v en
                                         «. £ v
                                       k o —
                                       ±*  .*
                                         5v e o
                                       -352

                                       •SS^£
                                       cy> A-O a
                       
                       kCJkO     kU  k       o 
-------
 Notemlgonus  crysoleucas.  respectively.   The  larval  sea lamprey,  Petromyzan
 marlnus.  however, suffered  no effects  at  5.0 mg/i  under  static  conditions
 for  24 hours  (Applegate et al., 1957).  Fathead minnow, Plroephales  promelas.
 embryos  1n mid-cleavage experienced  morphological  defects  and late  hatching
 at  concentrations of  0.1-5.0 mg/i  for  24  hours,  and  mortality and  reduced
 viability  at  1.0-5.0  mg/l   for  48  hours   under  continuous-flow  conditions
 (Henderson et al., 1981).
     The  effects  of   hydrazlne on  freshwater  toad  tadpoles  and  salamander
 larvae were  also  Investigated.    Greenhouse  (1976)  reported mortality  In
 "most" of  the  South  African  clawed toad, Xenopus laevls. tadpoles exposed  to
 concentrations  of  >1.0 mg/l for  24  hours;  all  died at  120  hours under
 static conditions.   Approximately half  of  the tadpoles survived exposure  to
 0.01  or  0.1  mg/i  for  120  hours.   Malformations were observed 1n 100% of  X.
 laevls embryos  exposed  to >25 rog/i  for an  unreported  length of time.  The
 threshold  level  for   the embryos   appeared  to   be  10  mg/i.    Similarly,
 Greenhouse  (1977)   reported   an   ED,.Q  of   12.5   mg/i  for  malformations
 observed   In  )(.   laevls  embryos  exposed  under static  conditions  from  the
 blastula   stage   to   hatching.    Spotted   and  marbled  salamander   larvae,
 Ambystoma  sp..  were  exposed  under  static   conditions  to  hydrazlne  in  both
 hard   (400-500  mg  CaC03/l)   and   soft  water  (20-25  mg  CaCO^/i)   (Slonlm.
 1986}.   As with  the  guppy (Slonlm,  1977),  hydrazlne was more  toxic to the
 salamander  In soft  water  than 1n  hard water,  with  corresponding  96-hour
 LCcns  of  2.3  and 5.3 mg/l,  respectively.   There was less  of  a  distinct
  bU
 difference at 48 and 24 hours.
    Fisher et  al. (1980b) examined  the  effects  of  hydrazlne on freshwater
 benthlc  crustaceans.    Amphlpods,  Hyalella  azteca.  and  Isopods, Aslllldae.
0325d                               4-5                              03/27/90

-------
 were  exposed  to hydrazlne  under  similar  static  conditions.   The  48-hour
 LC5n  for  H.  azteca  was  0.04  rog/i,  and  the  72-hour  LCcn  for  As 1 in da e
                                                           50
was  1.30 mg/l.
     Harrah  (1977)  studied the effects  of  hydrazlne exposure on  a  saltwater
fish,  the  stickleback.  Gasterosteus aculeatus.  The  Investigator  reported a
96-hour  static   LC5Q  of  3.4  mg/l.    However,   hydrazlne  concentrations
measured at  the  end  of  the  test indicated  significant  degradation  and that
the actual  LC   was probably lower.
4.1.2.   Chronic Effects on Fauna.
    4.1.2.1  TOXICITY -- Pertinent  data  regarding  the  effects  of  chronic
exposure of  aquatic  fauna  to hydrazlne  were not  located  In  the  available
literature dted 1n Appendix A.
    4.1.2.2  BIOACCUMULATIOH/BIOCONCENTRATION -  Slonlm  and  Glsclard  (1976)
measured the bloconcentratlon  of  hydrazlne  In gupples,  P. retlculata.  In
static  systems  using   hard   and  soft  water.    In   hard   water   (440  rag
CaCO_/i)  with   an   Initial   hydrazlne  concentration  of  0.5  mg/l,   the
    %J
96-hour wet  weight  BCF  was  288.   In  soft  water  (20  mg CaCO^/i) with  an
Initial  hydrazlne  concentration  of  0.25   mg/l.   bloconcentratlon  was  not
detectable.  Hydrazlne  may  have  low to moderate bloconcentratlon  1n fish  1n
hard water.
4.1.3.   Effects on Flora.
    4.1.3.1.   TOXICITY — Both  freshwater  and  saltwater  algae  were  tested
with  hydrazlne.    Harrah  (1977)  seeded  flasks  containing  hydrazlne at  0,
0.05,  0.50,  5.0  and  10.0 nl/1 of  SAAN undeY  simulated  ollgotrophU  and
eutrophlc  conditions with  the  freshwater  alga,  Selenastrum  caprlcornutum.
The  eutrophlc  conditions  (100%  SAAN medium)  yielded the  lowest  EC5Q,  0.006
pl/l  for  3  days;   however,  all  conditions   (10,  33 and  100% SAAN medium)
yielded  a   no-effect or  SC  level  of  0.001 yl/l for  3  days.    The  EC5Q
0325d
4-6
03/27/90

-------
 was  based  on algal  growth.   Seeding  with  the  saltwater  alga,  Punallella
 tertlolecta.   resulted   In  a  6-day  EC5Q  of  0.0008  wi/i  under  somewhat
 ollgotrophic  conditions  (10%  SAAM  medium)  and  0.0011   vi/i   under  inter-
 mediate  or estuarlan conditions  (33% SAAH medium)  (Harrah, 1977).   The SC
 levels  for  these  conditions  were  0.0005  and 0.001, respectively.  Because of
 evaporation  or degradation  of the  hydrazlne,  longer exposures  resulted 1n
 higher ECSQs.
     James  et  al.  (1987)  tested 10 saltwater phaeophyte (brown algae) species
 with  hydrazlne.   Mortality  was  observed  In  1-3  weeks  In  embryonic  sporo-
 phytes  (Cystoselra  osmundacea. Sargassum agardhlanum and  S.  mutUum) exposed
 to   hydrazlne  at  0.08  mg/i.   A  concentration   of   0.25  mg/i  for  1   day
 Increased  mortality  In  Hacrocystls  pyrlfera.  Gametophyte  growth  rate  was
 Inhibited   at  concentrations  of   0.025  mg/i   (Laminar la  dentigera.   I.
 ephemera  and  Nereocvstls  luetkaenal.    0.13  mg/l  (M.   pyMferal  and  0.25
 mg/l  (Elsenla arborea).  Sporophyte  production  was  affected In  H.  pyrlfera
 at  0.025 mg/i and  In  L.  dentlgera  and  1n L. farlowll  at  0.25  mg/l.   The
 gametophyte  growth  rate  of  L.  farlowll  and Pteryqophora  callfornlca  were
 unaffected  at  concentrations  of  0.25   mg/i.    James  et  al.   (1987)  also
 tested brown  alga with  hydrazlne.  S. mutlcum. S. agardhlanum  and C.  osmun-
 dacea  were exposed to  hydrazlne for  1  day,  and  growth  was measured.   The
 threshold  for toxldty  1n £. osmundacea  was  between 0.04  and 0.08 mg/l.
 Quantitative or qualitative results for the Sargassums were not  reported.
    4.1.3.2   BIOCONCENTRATION  — Pertinent  data   regarding   the  bloconcen-
 tratlon  potential  of  hydrazlne  in aquatic  flora  were not  located 1n  the
 available literature cited 1n  Appendix A.
 4.1.4.   Effects   on  Bacteria.  The effects  of  hydrazlne on bacteria  were
 Investigated  by  Kane  and Williamson  (1983).  The  substrate  metabolism rates
0325d                               4-7                              03/27/90

-------
 of NUrobacter.  NUrosomonas.  denitrifying bacteria and  anaerobic  bacteria
 were  reduced 50% by hydrazlne at  concentrations  of 14.6, 94.8, 65  and  145
 mg/l,  respectively.
 4.2.    TERRESTRIAL TOXICOLOGY
 4.2.1.    Effects   on  Fauna.    Pertinent  data  regarding   the   effects   of
 exposure  of  terrestrial  fauna  to  hydrazlne were not located In the available
 literature cited  1n  Appendix A.
 4.2.2.    Effects   on  Flora.    Pertinent  data  regarding   the   effects   of
 exposure  of  terrestrial  flora  to  hydrazlne were not located In the available
 literature cited  In  Appendix A.
 4.3.    FIELD STUDIES
    Pertinent data  regarding  the  effects of hydrazlne  on  flora  and fauna In
 the field were not located In the available literature cited In Appendix A.
 4.4.    AQUATIC RISK  ASSESSHENT
    The  lack  of adequate data  regarding the effects of  exposure of aquatic
 fauna  and flora  to hydrazlne precluded   the  development  of a  freshwater
 criterion  by the method of  U.S.EPA/OMRS  (1986)   (Figure  4-1).   Additional
 data required to  develop  a freshwater  criterion Include the results of acute
 assays  with  a  planktonlc   crustacean,  an   Insect,  a   nonarthropod  and
 nonchordate  species  and  an  insect  or  species  from a  phylum  not previously
 represented.   The development  of a freshwater criterion  also requires data
 from  chronic toxlclty  tests  with  two  species of  fauna  and at  least  one
 flowthrough bloconcentratlon study.
    The lack  of adequate data  regarding the effects of  exposure of aquatic
 fauna and flora to hydrazlne precluded the development  of a saltwater crite-
 rion  by the method  of  U.S.EPA/OURS   (1986)  (Figure 4-2).  Additional  data
 required for the  development of a saltwater  criterion  Include  the results of
acute  assays with   one   chordate  species,  a  nonarthropod and  nonchordate
0325d
4-8
03/27/90

-------
Family
#1
Chordate
(Gasterosteus aculeatus)

#2
Chordate
#3
non -Arthropod/ -Chordate
#4
Crustacean (Mysid/Panaeid)
#5
non-Chordate
16
non-Chordate
#7
non-Chordate
#8
other
#9
algae
fDunaliella tertiolectal

#10
Vascular plant

GMAV

3.4

NA

NA

NA

NA

NA

NA

NA
XXX

XXX
TEST TYPE
GMCV

NA

NA

NA

NA

NA

NA

NA

NA
0.0008*

NA

BCF

NA

NA

NA

NA

NA

NA

NA

NA
NA

NA
NA«Not Available
"=based on a  6 day  study
                                  FIGURE  4-1

     Organization  Chart  for  Listing  GMVs,  GHCVs and  BCFs  Required to  Derive
 Numerical  Water Quality Criteria by  the Method of U.S.  EPA/OURS (1986) to
 Protect Freshwater Aquatic Life from Exposure to Hydrazlne
 0325d
4-9
01/19/90

-------
                                                TEST TYPE
         Family
      GMAV
GMCV
BCF
          #1
   Chordate  (Salroonid-fish)
   fSalroo gairdneril
       6.0*
  NA
   NA
           #2
   Chordate  (warmwater fish)
   (Lebistes reticulatus)
        o.er
  NA
   NA
           #3
   Chordate  (fish  or amphibian)
   (Ictaluras puflctatus)
        1.00
  NA
   NA
           #4
   Crustacean  (planktonic)
       NA
           #8
      New Insectan  or phylum
       representative
       NA
  NA
  NA
   NA
#5
Crustacean (benthic)
(Hyalella aztecal
#6
Insectan
#7
non-Arthropod/-Chordate
0.04C NA
NA NA
NA NA
NA
NA
NA
   NA
           #9
         algae
   fSelenastrum capricornutunO
        xxxx
   0.006
   NA
           110
      Vascular plant
                    NA
              NA
  NA=Not Available
  a=based on a 76-hour  LC50
  b=based on a study with  soft water  (20-50  mg CaCO3/£)
  c«based on a 48-hour  LC«n
   Abased on a 72-hour  LCSO
                              FIGURE 4-2

    Organization Chart for Listing  GHAVs, GMCVs and BCFs Required to Derive
Numerical Mater  Quality Criteria by  the Method of U.S.  EPA/OURS (1986) to
Protect Saltwater Aquatic life  from Exposure to Hydrazlne
0325d
4-10
           01/19/90

-------
 species,  a mysld or panaeld  crustacean,  two  additional  nonchordate  species.
 and  one  other  species  of  marine  fauna.   The development  of a  saltwater
 criterion  win  also  require  data  from  chronic   toxlclty   tests  with  two
 species of fauna and at least one flowthrough bloconcentratlon study.
 4.5.   SUMMARY
    The   acute  toxldty   of  hydrazlne   was   examined  reasonably   well   In
 freshwater  fish.  Nevertheless,  data  regarding the  toxldty  to  freshwater
 Invertebrates  or  salt water  fauna  are  Insufficient, precluding  criterion
 development.   The  available studies,  however,  Indicate trends  In the  toxlc-
 lty of hydrazlne to  freshwater  fauna.  Including fish,  toads,  salamanders  and
 crustaceans.   Toxldty to  the  guppy  (Slonlm, 1977} and  salamander  (Slonlm,
 1986)  was Influenced by water  hardness,  with lower LC5Qs resulting  In  soft
 water.   Similarly,  Hunt  et  al.   (1981)   noted  an   Increase  1n  hydrazlne
 toxldty  In  bluegllls  at  24 hours corresponding  to an  Increase   In  water
 temperature.
    For  bluegllls,  catfish  and  shiners,  96-hour   LC5Q  levels were  1.0-1.6
 mg/i  (Hunt et al.,  1981;  Fisher et al.,  1980a,b,  1978).  Results  from  the
 Slonlm  (1977)  experiments  with hard and  soft water  yielded 96-hour  LC—s
 of  3.85   and  0.61 mg/i,  respectively,  for  the guppy.   The  rainbow  trout,
 however,  appeared  more  tolerant,  with  a   reported  76-hour  LC5Q  of  6.0
 mg/i   (Liu  and   Nakatanl,  1964).    Similarly,  Applegate   et  al.   (1957)
 reported  no  effects   In  larval  sea  lampreys  exposed to  5.0 mg/i  for  24
 hours.
    Other  effects  were  observed  in   freshwater   fish.    Southgate  (1950)
 observed  a  loss  of  equilibrium In  trout  finger lings  at  0.7 mg/i  at  24
 hours, and Fisher et  al.  (1978)  reported a  loss  of  balance 1n  bluegllls
 exposed  to  hydrazlne  at  concentrations   as   low  as  0.0010  mg/i  for   30
minutes.
0325d                               4-11                              03/27/90

-------
    The
               for  freshwater  toad  tadpoles was  0.01  mg/i  for  120  hours
 (Greenhouse,  1976).   However,  the LC5Qs  for  salamander  larvae were  8.0  and
 5.3  mg/t In  hard water  and 5.2  and  2.3 mg/t  In  soft water  at 48  and  96
 hours, respectively (Slonlm, 1986).
    Freshwater algae  were also tested with hydrazlne.   S.  caprlcornutum had
 the   lowest   EC5Q  (0.006   yt/l   for   3  days)  for   algal   growth  under
eutrophlc  conditions;  however,  a  concentration  of  0.001  yl/l  for 3  days
was  Indicated as  safe  for  ollgotrophlc,  Intermediate  and  eutrophlc  water
conditions (Harrah, 1977).
    The  saltwater  alga,  D.  tertlolecta.  was  exposed   to  hydrazlne  under
similar  conditions   (Harrah,   1977).    Ollgotrophlc   conditions   yielded  a
slightly   lower   6-day   EC™   (0.0008   ui/i)   than  estuarlan   conditions
(0.0011  yi/i).    Brown   algae   (phaeophytes).   sporophyte  and  gametophyte
growth  and  viability  were  affected  at  hydrazlne  levels  as  low  as  0.025
mg/t, (James et al., 1987).
    One saltwater  fish,  the stickleback, Gasterosteus aculeatus.  was tested
with  hydrazlne  (Harrah.   1977).   The  96-hour  LC5Q  was  3.4 mg/t,  similar
to  freshwater fish  LC5Q  values.   However,  the  author  suggested  that  the
actual
            was probably lower because of degradation.
0325d
                                    4-12
03/27/90

-------
                              5.   PHARHACOKINETICS

     Portions  of Chapters  5  and 6  of  this  document were taken verbatim  from
 the Health  and Environmental  Effects  Profile  for  Hydrazlne  and  Hydrazlne
 Sulfate (U.S.  EPA,  19845).
 5.1.    ABSORPTION
     Inhalation  exposure   studies   of  hydrazlne  are  difficult  to  conduct;
 hydrazlne  tends to condense  on  the walls  of the exposure chamber and on the
 skin  and coats  of  test animals.   Nonetheless,  hydrazlne  Is  apparently well
 absorbed by  the Inhalation  route.   Five-month-old male  F344  rats  weighing
 348ill  g were  exposed  for 1 hour  to  hydrazlne at  concentrations of  10, 60
 and 500 ppm in a nose-only Inhalation chamber (Llewellyn et al., 1986).  For
 comparison,  a   second  group  of  rats  received  Intravenous   Injections  of
 hydrazlne  of  2. 6  or  12 mg/kg.   Urine samples were  then collected*at various
 times  and  analyzed for excretion of  hydrazlne.   The percent recovery In the
 urine  of an  Intravenously administered dose  of hydrazlne  Increased  as  the
 dose  Increased;  14,  16 and 33X  of the hydrazlne was recovered at 2, 6 and 12
 mg/kg.  respectively.   After  Inhalation exposure, urinary excretion of hydra-
 zlne  in amounts comparable  with those  following  Intravenous  administration
 was observed  only  1n  the  500 ppm group.  Using urinary excretion as a basis,
 the authors  estimated that 500  ppm  was  equivalent  to an intravenous dose of
 9.8  mg/kg,  and estimated  an  Inhaled  dose  of  -8.3 mg/kg,  based on  body
 weight,  minute  volume  and duration  of exposure.   These  data  suggest  that
 absorption  of hydrazlne  1s  extensive from  the  respiratory tracts  of  rats.
 No  attempt  was made  to distinguish between the excretion  of  free hydrazlne
 or  Us metabolites, acetylhydrazlne and  dlacetylhydrazlne.
0326d                               5-1                              03/27/90

-------
     Inhalation  exposure  of male Sprague-Dawley rats to hydrazlne  at  concen-
 trations  between  13 and  24 ppm showed a  correlation  between  atmospheric  and
 blood  concentrations  (Dost  et  al..  1981).   The  value  of   these  data  1s
 limited,  however,  because  neither  the  regression coefficient nor a  quanti-
 tative summary of blood concentrations was reported.
    Pertinent  data  regarding gastrointestinal  absorption of  hydrazlne  were
 not located 1n the available literature cited In Appendix A.
    Hydrazlne  was  detected  1n  the  plasma  of dogs  within 30 seconds  after
 dermal  application   of  96,  118,   128,  160,  224,  320  or 480 mg/kg,  which
 Indicates that hydrazlne  Is  rapidly  absorbed  by  this  route (Smith and Clark,
 1972}.   Plasma  concentrations were  highly  variable,  but  dose-related  up to
 224  mg/kg,  and Increased  for  the first  40-60  minutes  until   a  steady  state
was  reached.   No  correlation was  observed  between  plasma  levels  and  the
 urinary concentration of  hydrazlne;  therefore,  excretion  data are not useful
to estimate dermal absorption.
    Hydrazlne was rapidly  absorbed  through  the  skin of  rabbits that  received
12 mg/kg  of  either  anhydrous hydrazlne  or  H-70, an aqueous  solution  of  70%
hydrazlne  (Keller et al.,  1984).   The  chemical was applied  for 2,  6  or 12
minutes and  then  washed  off  with  a dilute hypochlorlte  solution.  A direct
correlation  was  observed  between   time  of  exposure  and serum  levels  of
hydrazlne.  Peak  serum levels were  reached  in 50-90 minutes  with anhydrous
hydrazlne  and  in  30-50  minutes  with  H-70.   Total   absorption  directly
correlated  with duration  of  hydrazlne  exposure;  the  total percentage of
absorption was  87 and 55% for anhydrous  hydrazlne and  H-70, respectively.
Hydrazlne  caused  severe  chemical  burns  that  may  have  altered  the  rate of
absorption.   When   the   surface   vasculature  1s  damaged,   hydrazlne  must
penetrate  deeper  to  reach the Intact  vasculature, and  absorption will be
0326d
5-2
01/19/90

-------
 delayed.   This  explains  the decrease In the rate of absorption between 2 and
 6  minutes.   In  the  same  study,  another  group  of  rabbits was  exposed to
 either  2  or   15%  aqueous  hydrazlne.    Peak  serum  concentrations   of  3.1
 yg/mi   for   2%,  and   5.6   jjg/mi   for   15%  aqueous  hydrazlne  were   reached
 within  10  and  30 minutes,  respectively.  There were no chemical burns asso-
 ciated  with  application of  these  solutions;  apparently, damage  to the skin
 Is  not  a  prerequisite  for  absorption  of hydrazlne.   Serum concentration
 continued  to Increase with time for  all  hydrazlne  solutions after they were
 washed  off.    The  authors  concluded  that  this   observation  Indicates  an
 epidermal  compartment;  their  calculations  revealed   that  66-75%   of  the
 percutaneously  absorbed  hydrazlne  Is  still   In  the  epidermal  compartment
 after 2 minutes of exposure.
 5.2.    DISTRIBUTION
    Tissue distribution  of hydrazlne was studied 1n  male Swiss Webster mice
 after  a single IntraperHcmflal fhjectlon  of  32 mg/kg  (Nelson  and   Gordon,
 1982).  Hydrazlne was rapidly  distributed  to most tissues,  but  time course
 data were  not  presented.   At  2 hours,  the highest  levels  of hydrazlne were
 found  In  the kidney  (22.8*2.6  wg/g) and the next  highest  levels were found
 In  the spleen  (7.8±2.1   yg/g)   and  lungs   (7.0+1.0  wg/g).   The  lowest
 levels  were  observed  In  the  brain  (2.5+0.4 wg/g).   At 24  hours,  the
 pattern of  tissue distribution was  the same, but  levels had fallen  to "10%
 of the  2-hour values.
    Similar  results  were  observed  1n male Sprague-Oawley  (Holtzman   strain)
 rats  injected  subcutaneous1y  with  60  mg  hydrazlne/kg   {Dambrauskas  and
 Cornish, 1964).   Tissue  levels  of  hydrazlne were  measured at 2 and 20 hours;
 the  highest   levels   were   found  1n  the  kidney  (56.4  vg/g),  spleen (18.6
 ug/g)  and   lungs   (16.2  yg/g).   The  same  pattern of   tissue  distribution
was observed at 20 hours, but levels had fallen to -10% of the 2-hour values.
0326d                               5-3                              03/27/90

-------
     Hydrazlne  was rapidly distributed In male VJIstar rats after subcutaneous
 Injection  of  9.92  mg/kg (Kaneo et  a!., 1984).  Maximum  tissue  levels were
 found  at  0.5 hours; the greatest concentration was found In the kidney.  The
 elimination  half-lives  for  hydrazlne In kidney,  liver,  lung and  plasma were
 2.7. 3.3, 3.0  and 2.3 hours, respectively.
    The rate of  hydrazlne distribution  to tissues can also be estimated from
 the data  of  Springer et  al.  (1981).  The peak plasma level In rats occurred
 almost  Immediately  after Intraperltoneal Injection of 32 mg hydrazlne/kg and
 was  followed  by rapid  distribution to  the  tissues;  the  calculated  t, ,„
                                                                         l/2a
 was 0.74 hours.
 5.3.   METABOLISM
    Springer et  al. (1981)  Investigated the metabolism  of  hydrazlne In male
 Sprague-Oawley rats after Intraperltoneal  Injections of 16,  32 or 48 mg/kg.
 A  slight  Increase  In the production of N.  gas  was  observed with Increasing
 dose.   In  the first  30  minutes  following  hydrazlne Injection of 32 mg/kg,
 15% was  converted  to N» gas,  and  by  48 hours,  25% had  been converted  to
 Np  gas.   After  Injection,  hydrazlne and  hydrazlne derivatives   were  found
 1n  the blood  and  urine  of the  rats; however,  except  for  small  amounts  of
 acetylhydrazlne  and dlacetylhydrazlne,  the  derivatives  were not   Identified.
 About  52%  of the Injected  dose  was  found  in  the urine; about half of this
 quantity was hydrazlne.   Less  than 1% of the  Injected  dose of hydrazlne was
 found  In the bile.
    The route  of  Injection may  Influence   the  extent  of  N-  gas  production
 because slightly less N. gas  was  formed  after  subcutaneous  injection than
after  Intraperltoneal  and  intravenous  Injection (Springer  et al.,  1981).
0326d
5-4
03/27/90

-------
 The formation  of  N2  gas  may  occur  In  the  erythrocytes; jn.  vitro Incuba-
 tions  of whole blood  with  hydrazlne  revealed  that -50% of the hydrazlne was
 converted  to  Np gas  1n 3 hours.
     Nelson and Gordon (1982) reported that oxyhemoglobln  In whole blood from
 Swiss   Webster mice  Is  capable   of   oxidizing   hydrazlne  to  N_  gas  and
 suggested  that this mechanism  causes  the Initial  rapid decrease  In  blood
 levels  of hydrazlne.   Furthermore, acid  labile  conjugates  1n  the  urine  of
 Swiss  Webster  mice  Injected  Intraperltoneally  with 32  mg/kg  accounted  for
 25% of  the  dose;  these have  been Identified as  acetyl- and  dlacetylhydra-
 zlne,  pyruvlc  and  oxoglutaMc  add  hydrazones, and a tetrahydrooxopyrldazlne.
     Kaneo  et  al.   (1984)  observed  that.  In  male  Wlstar rats.  -30% of  a
 hydrazlne  dose  (9.92 mg/kg)  Injected  subcutaneously  was recovered 1n  the
 urine  as hydrazlne and Us  N-acetylated metabolites, monoacetylhydrazlne and
 dlacetylhydrazlne:  82% as  hydrazlne,   10% as  monoacetylhydrazlne and  8%  as
 dlacetylhydrazlne.   The relative rates of N-acetylatlon and N-deacetylatlon
 will determine the extent of hydrazlne acetylatlon.
    Male  albino Swiss mice  were used  to  determine  the  metabolism  rate of  a
 single  subcutaneous  Injection of  hydrazlne (Dambrauskas and  Cornish.  1964).
 Mice received  40,  60.  80,  90  or 100 mg  hydrazlne/kg and were  sacrificed  at
 various  time   points  0.5-48 hours  after   Injection.   The  difference between
 the  amount of hydrazlne  Injected and  that  recovered  from  the urine  and
 carcass  was  considered to  represent  metabolized hydrazlne.   Most of  the
 hydrazlne was  metabolized within 0.5 hours of  Injection (41.1% at 100 mg/kg,
 increasing  with decreasing   dose to 63.5% at  40 mg/kg).  Little  metabolism
 occurred  later than 2  hours after  treatment.   Between  47 and 48% of  the  40
 and 60  mg/kg  doses were excreted as hydrazlne  In  the urine  within  48 hours.
0326d                               5-5                              03/27/90

-------
After  48 hours,  only 0.3 and  1.4% of  the  40 and  60 mg/kg doses,  respec-
tively, were  recovered  In  the carcass;  virtually  no  hydrazlne  remained  at  72
hours.
    HcKennls  et al.  (1959) reported  a  difference  between  rabbits  and dogs  In
the ability  to produce dlacetylhydrazlne.   In  rabbits Injected Intraperlto-
neally  with   (24  mg/kg)  hydrazlne,  10%  of  the dose  was  recovered  from the
urine  as  hydrazlne  and  monoacetylhydrazlne  and  2.5% as  dlacetylhydrazlne.
In dogs Injected  Intravenously with  50  mg/kg,  6.6% of the dose was recovered
as hydrazlne and monoacetylhydrazlne, but no dlacetylhydrazlne was found.
5.4.   EXCRETION
    Nelson and Gordon (1982) accounted  for as  much as 75% of a single Intra-
perltoneal Injection  of  32 mg  hydrazlne/kg  1n  Swiss  Webster  mice.  Within 2
hours,  20%  of the  Injected  dose  was  converted  to  N_ gas. and  another 15%
was converted to  N. gas over the  next  46 hours.  About  15%  was  excreted  1n
the urine as unchanged hydrazlne and 25% as acid  labile conjugates.
    Male  Sprague-Dawley  rats   excreted  -52%  of a   single  1ntraper1toneal
Injection of  32  mg hydrazlne/kg  In  the urine  as hydrazlne and metabolites,
and 25% was   exhaled  as  N?  within  48 hours  (Springer  et al.,  1981).   The
rate  of  urinary  excretion of  hydrazlne and  Its  derivatives was  >5% of the
dose/hour Immediately after  Injection;  this  decreased to 0.25% by 48 hours.
Less  than  1%  of  the Injected dose  was  excreted  Into bile.   The calculated
t1/2B was 26.9 hours.
    Dambrauskas and Cornish  (1964)  observed  that 47-48%  of  subcutaneous1y
injected hydrazlne  was  excreted in  the urine within  48  hours.  HcKennls  et
al.  (1955)  recovered 3-20%  of  a  single  Intravenous dose  of  50  mg hydra-
zlne/kg In the urine  of  dogs within  8 hours; however, all but one of the six
0326d                               5-6                              03/27/90

-------
 dogs  tested  died  before  the  8-hour collection  point.   About  50% of  a  15
 mg/kg  dose of  hydrazlne Injected  Into  dogs was recovered  within  48 hours.
 No  hydrazlne  was detected  1n saliva  or vomHus  (McKennls et al., 1955).
 5.5.    SUMMARY
    Hydrazlne appears to  be  absorbed extensively by  the  respiratory tract;
 similar  doses  administered  to rats  by  Inhalation  or  Intravenous  Injection
 resulted  In  equivalent  urinary  excretion  values  (Llewellyn et  al.,  1986).
 Blood  levels  of hydrazlne  Increased for  60-120 minutes In  rats after Inhala-
 tion  exposure;  however,  the  correlation  between atmospheric  concentration
 and blood  levels  was weak (Dost  et  al.,  1981).  Hydrazlne was  detected  1n
 the plasma  of dogs within 30  seconds of dermal application, Indicating that
 hydrazlne   Is   rapidly  absorbed  by  this   route (Smith  and  Clark,  1972).
 Similar  to  the Inhalation exposures  reported  by Dost et  al.  (1981),  plasma
 concentration  and  the  dermally  applied dose  were   weakly  correlated  (Smith
 and Clark,  1972).  Hydrazlne was  also rapidly  absorbed after dermal applica-
 tion In rabbits; the total  percentage  of  absorption  1n rabbits  was  87% for
 anhydrous hydrazlne,  and 55X for  70X aqueous hydrazlne (Keller et al.. 1984).
    Tissue  distribution  of hydrazlne after  1ntraper1toneal  and subcutaneous
 Injection was rapid   In  rats and  mice (Nelson  and Gordon,  1982;  Oambrauskas
 and Cornish,  1964;  Kaneo  et  al., 1984).    Peak  tissue  levels were  reached
within  0.5-2  hours.   The highest  levels  were found  in the  kidney, spleen and
 lungs;  the  lowest  levels were  found 1n  the brain,  muscle and fat (Nelson and
 Gordon, 1982;  Dambrauskas  and  Cornish,  1964; Kaneo  et al.,  1984).   The rate
 of  distribution can  be estimated from  the t:,/2   (0.74  hours)  calculated
 by  Springer et al. (1981).
    Metabolism  studies Indicate that  1n  rats and mice, hydrazlne Is excreted
 largely unchanged  In the  urine or as N.  gas  after  oxidation  by hemoglobin


0326d                               5-7                              03/27/90

-------
(Springer  et al.,  1981; Nelson  and Gordon,  1982).   Small  amounts  of  the
N-acetylated  metabolites,  acetyl- and   dlacetylhydrazlne,   have   also   been
Iden-  tlfled in  urine.   Nelson and  Gordon  (1982) reported  that  25% of  an
Injected dose of  hydrazlne  Is  converted  to add  labile  conjugates.  McKennls
et  al.  (1959)  reported  that  rabbits excrete  primarily unchanged  hydrazlne
and  smaller  amounts of  the mono- and d1-N-acetylated  derivatives;  however,
dogs do not  excrete dlacetylhydrazlne.   Less than 1% of an  Injected  dose of
hydrazlne was excreted  Into bile  (Springer  et  al.,  1981),  and no  hydrazlne
was found 1n saliva or vomltus (McKennls  et  al.,  1955).
03264
5-8
03/27/90

-------
                                  6.  EFFECTS
 6.1.    SYSTEMIC TOXICITY
 6.1.1.    Inhalation Exposure.
     6.1.1.1.    SUBCHRONIC  — Groups   of  50  male  Sprague-Dawley  rats,  40
 female  ICR mice, 8 male beagle dogs and 4  female  rhesus  monkeys  were  exposed
 by  Inhalation  Intermittently  (6 hours/day,  5  days/week)  to  1.0 or  5.0 ppm
 (1.3  or  6.6  mg/m3)  hydrazlne  or  continuously  to  0.2  or 1.0  ppm (0.26 or
 1.3 mg/m3)   for  6  months  (Haun  and  Klnkead,   1973).    Unexposed   control
 groups  of the  same  size were  used.   Toxlclty parameters  that were evaluated
 Included  body  weight  (rats,  monkeys  and  dogs),  clinical  chemistry  (five
 rats/group,  dogs and monkeys),  hematology  (dogs  and monkeys), organ  weights
 (rats,  monkeys  and dogs) and histology (all animals).  Significant mortality
 occurred only  In  the  mice,  was dose-related and  occurred In most Instances
 during  the first 2-2.5 weeks of  exposure;  total  mortality 1n the 0 ppm, 0.2
 ppm continuous,  1.0  ppm  Intermittent,  5.0 ppm  Intermittent  and 1.0 ppm
 continuous exposure groups was  0,  2.5, 7.5, 35  and 55X, respectively.  The
 mice were not weighed,  but rats exhibited a dose-related  growth  rate  depres-
 sion  (presumably at  all  exposure levels),  and  dogs lost weight  at  the two
 highest  exposure levels (1.0 ppm continuous  and  5.0 ppm  Intermittent).  The
 rat  and monkey  clinical  chemlstry/hematology measurements were  normal, but
 dogs exposed  at the two highest  levels had depressed red blood cell  counts,
 decreased  hemoglobin   values  and  hematocrlts,  and  Increased  erythrocyte
 fragility.   The  results  of  the  pathological  examination  showed  that the
 mortality  1n  the mice was  probably due to hepatotoxlclty; fatty  liver change
 was a  consistent finding  1n  the mice at all exposure  levels,  and slight to
 moderate  fat  accumulation was  noted In  the exposed monkeys  (presumably at
 all  levels).    Treatment-related  gross  or  hlstopathologlc effects  were not


0327d                               6-1                              03/30/90

-------
 described  In the other  species  at the  end  of  exposure, but  high-dose  mice
 {1.0  ppro continuous and 5.0  ppm Intermittent)  that were alive  1  year  post-
 exposure (six to nine/group) developed alveolar  carcinomas.
    Two  dogs and 20 rats  (strain  and sex not  specified)  were  exposed  to  6
mg/m3  (4.6  ppm)  hydrazlne  for  6  hours/day,  5  days/week  for  31  weeks
 (Cornstock and  Oberst,  1952).  One  dog  and 10 rats served  as  controls.   The
treated  dogs  lost   16  and  29X of  their  body weights,   respectively.   No
effects  on  body weight were  observed among  rats.   Muscle  tremors,  weakness
and  vomiting occurred  In  dogs  after  11  weeks of  treatment.   Rats  became
 lethargic after  23  weeks,  and  two  rats  died  during week 28.  Hydrazlne expo-
sure  had no effect  on  blood counts  and blood  chemistry among  the  animals.
 Interstitial  pneumonltls  with  localized areas  of  alveolar emphysema  among
rats and emphysema and atelectasls  In dogs were observed at autopsies.
    Comstock  et al.  (1954)  exposed 30 male  Wlstar   rats,  20  female  mice
 (strain  not  specified),  10 guinea  pigs  (strain and  sex not specified) and 4
male  beagle dogs  to 18  mg/m*  (13.7 ppm)  hydrazlne  vapor  6  hours/day,  5
days/week for  <6 months.   By  the  end of  the  treatment period,  23  rats, 15
mice,  8  guinea  pigs  and  2 dogs  had died.   Necropsies  (not  characterized)
were conducted  on the surviving  mice  and dogs,  but not on the other animals;
the mice reportedly showed no  abnormalities,  but  the  dogs exhibited hlsto-
loglcal  fatty changes in the liver  and spleen.
    Eight male  guinea pigs  were exposed  to  3-6 mg/m"  (2.3-4.6 ppm) hydra-
zlne  for 6  hours/day.  5 days/week for  2 weeks (Meatherby and  Yard, 1955).
After  2  weeks, the concentration of  hydrazlne  was  raised  to 4-8  mg/m*
 (3-6.1 ppm),  and exposure continued  for an additional  8 weeks.  Four guinea
pigs served  as  controls.   At  the termination  of the experiment, pathological
changes  were observed  1n   the  lungs  (lymphold hyperplasla,  atelectasls and
0327d
6-2
01/22/90

-------
 chronic   Inflammation)   of  exposed  animals.   Mongrel  dogs  were  exposed
 simultaneously  with the guinea  pigs.   Two dogs exposed  to  3-6 mg/m' at the
 beginning  of  the experiment showed signs of toxldty; they were killed after
 7  days.   Another pair of  dogs  was used later 1n the experiment for 28 days.
 Pathological  changes found  In  the first pair  of  dogs Included central-zone
 fatty  degeneration  of  the  livers, with zones of necrosis and accumulation of
 bile pigment.   Apparent  capillary damage In the kidneys and small patches of
 atelectasls  In  the lungs  were  found.   The second  pair of  dogs exhibited
 changes  only  In the livers; these changes were similar to those found In the
 first  pair.
    6.1.1.2.    CHRONIC —  The   value  of  ep1dem1olog1c   studies   In  workers
 occupatlonally  exposed  to  hydrazlne  1s  limited.   The studies were  done In
 factories  where either  other   chemicals  besides  hydrazlne were  present, or
 the exposure  levels were  n«t  documented.  An  unpublished  study  reported an
 Increased  Incidence  of  myocardlal  Infarcts  among  workers   occupatlonally
 exposed  to hydrazlne during the  years  1953-1978  In comparison with U.S. Air
 Force  and  U.S.  Public  Health   Service  data (Olln  Corporation,  1979).   This
 conclusion was  based on only five  confirmed  cases  of myocardlal   Infarction,
 and the  study was  not  controlled for  confounding variables such as preexist-
 ing  hypertension,  cigarette  smoking,  high  cholesterol,   lack   of  regular
 physical  exercise,  obesity, personality  type, medical  history  or  dietary
 factors.   In  an extension of   the  first  study Involving workers  exposed to
 hydrazlne  during  1953-1985,  no  new  cases  of  myocardlal  Infarction  were
 observed;  the investigator  concluded  that the association In the first study
 had occurred by chance (Olln Corporation. 1986).
    Nonneoplastlc  effects  of chronic  inhalation exposure  to  hydrazlne  were
 briefly  described  by MacEwen  et al.   (1981).   In  this study,  groups  of 100


0327d                               6-3                              03/30/90

-------
 rats/sex,  400 female mice or 4  beagle  dogs/sex  were exposed to 0.05-5.0 ppm
 {0.06-6.6  mg/m3} hydrazlne  for  1 year  (Section 6.2.}.   Reduced  growth and
 average  body  weights  were   reported   1n  all  exposed  rats,  compared  with
 controls.   The  effect  was  most  significant  In  male rats  at  5.0  ppm.
 Inflammatory  changes of  the respiratory  tract  were  prominent  In  the  rats
 exposed  to 5.0  ppm hydrazlne.   Respiratory effects  were  observed  In  rats
 that  died  during  exposure,  as  well  as  in  those  at the  2.5-year  terminal
 sacrifice, and were noted at exposure  levels  as low as  0.05 ppm In the male
 rats  (laryngeal/tracheal  Inflammation  and  nasal/lung hyperplasla)  and 1.0
 ppm  In  the  female  rats  (tracheal  inflammation).    Significantly  (p<0.05)
 Increased  Incidences of  other  nonneoplastlc  lesions were  described  1n the
 treated  rats  and Included lymph  node  hyperplasla, glomerulonephrosls, ovary
 atrophy, salp1ng1t1s and  endometrltls  1n the 5.0 ppm females, and myocardlal
 degeneration  1n  the  1.0 and 5.0 ppm males.  Exposure  to   hydrazlne  had no
 effect on  survival, growth,  body weight  or the  Incidence  of  nonneoplastlc
 pathological  lesions  1n mice.   In dogs, exposure  had no effect on survival,
 clinical  chemistry, BSP  retention  time or  the  Incidence  of  nonneoplastlc
 pathological lesions.
    Nonneoplastlc  effects after  a  1-year  exposure  of  male Syrian  golden
 hamsters  (200/group) to  0,   0.25,  1.0  and  2.0  ppm  (0. 0.32,  1.3  and 6.6
mg/m*}  of   hydrazlne were  also  recorded  (MacEwen  et  al.,  1981}  (Section
 6.2.}-   The  animals were  sacrificed  after  a  1-year  observation  period.
 Amyloldosls  In  the  livers,  spleens,  kidneys,  thyroids  and  adrenals, liver
 hemoslderosls, kidney mineralization,  senile atrophy and hypospermatogenesls
were found 1n all exposed groups.
 6.1.2.   Oral Exposure.
    6.1.2.1.   SUBCHRONIC — Groups  of  10 male  albino rats  were  maintained
on drinking  water   containing  hydrazlne at  0,  0.1,  0.2. 0.5,  1  or  2 rag/mi
0327d
6-4
03/30/90

-------
 for <14 weeks (Heatherby and Yard, 1955).  The average dose of  hydrazlne was
 estimated by  the  Investigators (for  the two lower  treated  groups) or from
 data provided by  the Investigators  (for  the three higher groups)  to be 0,
 15, 25, 57, 93 and  143  nig/kg/day, respectively.   At the end of week 3, half
 of   those  receiving  1   mg/mi   were   killed   and   examined;  the  rest  were
 continued on drinking water without hydrazlne.  Groups receiving 0.2 and 0.5
 mg/mi  were  treated   similarly  at   the end of week  4.   The  experiment  was
 terminated  after  14  weeks  of exposure.   Mortality  was  reported  In  all
 exposed groups;  three rats  In  the 0.1 mg/mi  group died In  the 5th and 6th
 weeks   of  exposure.    HlstopathologUal  examination  of  heart,  lung,  liver,
 spleen,  stomach,  small  Intestine,  kidney,   adrenal,   pancreas and  testes
 revealed  no chemical-related effects.  Growth was  Inhibited  In all treated
 animals;  this was due to  restricted  water  Intake  rather  than  to  hydrazlne
 toxlclty.
     In  a  study  of  the  carclnogenlclty  of hydrazlne sulfate,  groups  of  21
 male and  21  female   8-week-old  CBA/Cb/Se mice were treated by gavage with
 1.13 mg  hydrazlne  sulfate/mouse/day   for  36  weeks  (Sever!  and  Blandflorl,
 1968).  Assuming  a body weight  for mice  of 0.03  kg (U.S.  EPA,  1980),  a dose
 of  9.3 mg  hydraz1ne/kg/day can be estimated.  Observations  continued until
 natural  death  or  until  the mice  were moribund  and killed.  Both males  and
 females  In the treated group exhibited substantially Increased Incidences  of
 lung and  liver  tumors.   In  addition,   treatment with  hydrazlne sulfate
 markedly  reduced the  Hfespans of mice with or without lung or liver  tumors.
     Administration of hydrazlne sulfate by gavage  to  Syrian  golden  hamsters
 was  associated with  the  development of severe liver lesions (cirrhosis, bile
 duct  proliferation,  and  pressure  atrophy and degeneration of  hepatocytes)
 and  shortened  llfespans  (B1anc1f1or1, 1970a).   Treatment was  with  3.0  mg


0327d                               6-5                              03/30/90

-------
 hydrazlne  sulfate/hamster  for  60  treatments  during  15  weeks  or  2.8 mg hydra-
 zlne  sulfate/hamster  for  100 treatments during 20  weeks.  Assuming  the body
 weight  of  hamsters was 0.14 kg  (U.S.  EPA.  1986b),  TWA doses of  3.0  and 3.5
 mg  hydrazlne/kg/day  can   be estimated  for  the  two   treated  groups.   The
 animals were then maintained until moribund or dead.
    6.1.2.2.   CHRONIC — Pertinent  data  regarding nonneoplastlc  effects  of
 chronic oral exposure of  humans or  animals  to  hydrazlne  were not located In
 the available literature cited 1n Appendix A.
 6.1.3.   Other  Relevant  Information.   Several  acute  animal  studies  were
 located.   Acute  4-hour  Inhalation  LC,.s for  hydrazlne were  reportedly 252
 ppm  (330  mg/m3)  for  mice and  570  ppm  (747  mg/ma)  for  rats  (Jacobson  et
 al.,  1955).   The  animals  died  In  terminal  convulsions.   Pulmonary hemor-
 rhages  and  edema  and  CNS  hemorrhages  that  were  due  to  convulsions  were
 observed.
    Liver  DNA, which  was  methylated  at the  guanlne position, was observed 1n
male  Fischer rats  given hydrazlne orally at 60  or  90  mg/kg  and killed 13 or
 24 hours after administration (Barrows and Shank, 1981).
    Groups of  20 male  ddY mice  and male Hlstar  rats were  maintained  on a
 diet  containing  0,  0.5.  1.0 or  2.OX  of  hydrazlne  for 3 days  and  then on a
 regular diet for the  remaining  time  (Uakabayashl  et al..  1983).  The animals
were  killed  24, 48  and  72  hours after  the  treatment with  hydrazlne.   The
 Induction  of megamltochondrla  was  observed  In mouse  and  rat  hepatocytes
after the  treatment,  but  the process  was reversible.   Also, the activity of
 some  enzymes   (ATPase,  cytochrome   oxldase  and   monoamlne  oxldase)  was
 decreased  after  the  hydrazlne diet.   The  changes  Induced  by  hydrazlne in
mltochondrlal  membranes  were  further  Investigated   (Hakabayashl   et  al..
 1987).   Male Wlstar  rats  (number  unspecified)  were   maintained on  a diet
0327d
6-6
03/30/90

-------
 containing 0 or  IX  hydrazlne  for 3 and 7  days.   Assuming for rats that  the
 average body weight was  0.35  kg  and  food  consumption  was  5%  of the body
 weight  of the animal  (U.S.  EPA, 1986b), these  doses  correspond  to 0 and  50
 mg/kg/day.   Hlstopathologlcal  and chemical  changes were compared to those  1n
 control animals.   The  authors   suggested  that, after  megamltochondrla  are
 formed, the  mitochondria!  membranes  are  stabilized,  as  Indicated  by  the
 decrease  1n  changes  Induced  after 7  days of hydrazlne  Intoxication.
    Several  human case studies  on hydrazlne  exposure were  located,   field
 (1965)  described  a case report of a man who  swallowed an  unidentified amount
 (between  a mouthful  and a  cup)  of hydrazlne by accident.   The  patient was
 vomiting,  Incontinent,  and  unconscious soon after  the accident.   Within 2
 weeks   of  treatment,  his  condition  Improved,   but  ataxla  and  paraesthesla
 persisted.
    A  similar  case  of  a young man  who swallowed a  mouthful of  hydrazlne by
 accident was reported  by Haratl  and Nlakan  (1986).  The man became confused,
 lethargic  and   restless  soon   after   the   accident,  and   liver  function
 deteriorated.   After treatment  with megadoses  of  pyrldoxlne, his condition
 Improved.   One week after  the  therapy,   paresthesla and  other  neurologic
 signs remained.
    A 59-year-old machinist  who  handled hydrazlne once a week for the last 6
 months  of  his  life  was  frequently  tired and had conjunctivitis  and tremors
 after exposure  (Sotanleml et  al.,   1971).  He  was admitted  to  the hospital
 with upper abdominal pain, black feces and Icterus,  and died within 15 days
 of  hosp1ta11zat1on.    Severe  tracheltls,   bronchitis  and  lobar  pneumonia,
 toxic nephrosls,  focal  hepatocellular  necrosis  and  nonspecific  degeneration
 of heart muscle fibers were all found on autopsy.
0327d
6-7
03/30/90

-------
     Two  cases  of  contact   dermatitis   during   professional   handling  of
 hydrazlne  1n  a  gold-plating  bath procedure  were  described by  Hrangsjo and
 Martensson   (1986).   When  removed  from  exposure,   the  workers  completely
 recovered.
     Twelve  of 34 women contracted an  occupational  eczema after Introduction
 of  a new flux  containing  hydrazlne  hydrochlorlde Into  their  working proce-
 dure  (Frost  and  Hjorth,  1959).   One-half of  the patients  showed positive
 patch-test   reactions  with  hydrazlne  sulfate,    They  all  recovered  after
 discontinuing the exposure.
     Hydrazlne hydrobromlde  solder flux caused contact dermatitis among women
 workers  exposed during soldering In an  electronics  plant (Wheeler  et  a!.,
 1965).  Patch tests were positive 1n all workers.
    The  odor  thresholds  for  hydrazlne  were obtained  from  a  group of  16
 people.  The median  detectable concentration was a calculated  3-4 ppm.   The
 odor was described  as  ammoniac a 1 or fishy  by most of the subjects (Jacobson
 et  al.,  1955).  Ruth  (1986)  reported  odor  thresholds for hydrazlne  of 2.3
 ppm  (low) and 3.1 ppm (high).
 6.2.   CARCINOGENICITY
 6.2.1.   Inhalation  Exposure.   A  cohort  of  406  men  occupatlonally  exposed
 to  hydrazlne was studied by Uald (1985).  The levels  of exposure, although
 not  measured during  those years,  were an estimated  1-10 ppm (1.3-13 mg/ma)
 1n  the  general area with  peaks  of  <100 ppm (<130  mg/m") of  hydrazlne,  as
estimated by  the simulation of  spillage.   The mortality among workers during
                                               f
 the  1945-1971  period did  not differ from  the expected numbers  for any cause
of death.
    In an  occupational  control study,  14 cases  of soft-tissue  sarcoma  were
reported among  37,000 workers  In a chemical  plant  (Sobel et  al.,  1987). The


0327d                               6-8                              07/26/90

-------
 workers were  exposed  to several  different  chemicals  In this plant, but there
 was  no  association between any of  these chemicals.  Including  hydrazlne,  and
 the  Incidence of sarcoma.
     An  extensive  study was  sponsored  by  the A1r  Force  Aerospace  Medical
 Research  Laboratory (Carter  et  al.,  1981; HacEwen  et al.. 1981;  Vernot  et
 al.,  1985)  on the  oncogenlc  effects  of Inhalation  exposure to  hydrazlne  on
 several animal  species  (Table 6-1).  F344 male and  female  rats, male Syrian
 golden  hamsters,  C57B1/6 male  and female mice,  and male  and female beagle
 dogs  were used  In the  experiment.   The  animals  were exposed  to hydrazlne
 vapor  1n  concentrations of 0.05, 0.25, 1.0 and 5.0  ppm (0.06, 0.33,  1.3  and
 6.6  mg/m3)  for  rats  and hamsters, 0.05,  0.25 and  1.0 ppm (0.06, 0.33  and
 1.3  mg/m3)  for  mice,   and  0.25  and 1.0 ppm  (0.33  and  1.3 mg/m') for  dogs
 during  12 months  (6 hours/day, 5 days/week).  Hatching  controls were avail-
 able  for  all  species.   All the animals were  then  held for  a 12- to 38-month
 latency period, and an  extensive  examination  of  each animal. Including gross
 and  hlstologlcal necropsy,  hematologUal tests and overall  growth and weight
 gain, was performed at  the time of natural  death or at the  termination  of
 the  study.  An  Increased Incidence of nasal  benign  (adenomatous polyps)  and
 malignant (squamous  cell carcinomas)  tumors  was  reported  1n rats  after  the
 5.0  ppm  exposure,  while hamsters  developed  a higher  rate of  benign  nasal
 polyps  and  thyroid adenocardnomas than controls.   A statistically signifi-
 cant  Increase of  pulmonary adenomas was found 1n  the 1.0 ppm  group of mice.
 No oncogenlc  effect of  hydrazlne was  observed 1n  exposed dogs;  the duration
 of treatment  and  the  duration of study was  not  sufficient to  see carcino-
 genic  effect.   The data   from  these  studies did   not  provide  sufficient
 evidence  In support of  carclnogenUUy of  hydrazlne  by  the Inhalation route
 of exposure.

0327d                               6-9                              07/26/90

-------
t|i

*"££

a.
H-
1
m ^
M
m
L.
t_
•*-»
§ e.

i
o •—
.a .V u 4)
V u vi 10
*l — »»•*
1 *°"
W
(A
I "I
m k, B
3 5
vi a. o
k.
41
.*«
i i-5"v?
>  B
M k, e
u
u <^
I ill
v» IV O O
k. k. k. •
k-
tb
e
u e
1 tl^
U tf* k •
£ Scl
K tl M
w
M
,.
Si
£"

ff* 1/1 (B i/l »-» r— *—
f- O r- r*- O «O GOO m O

1111
e B B s
1 1 I Is Is Is 11
E B •- eeeeeeec

£ £ S S
-f> 0 U U O
o> o> ^ "iv *o *v  M vl
s e « ia « *
_ _ ,, c B B E

•O
^ ^.
22
». **


R S S S S S S

CM « CW n >» ^^ >« >«

r~ »
^ ^
u ^J
X «
K crt «« 
— — » V Z
vn — — • —
vi o o r» &t
B| i S ^ i i i
1 111111
E 5^5555

See c e ee c c BE Be
4> 41 41 41 4141 41 4) 4t 41 41 V

^ j; ^ s s s


" c c c c c c

•o -o
5 •*- 5 ^
2e >« e
k. Ok,

IV « « >V 3U3W

g g g 0 £ 0

CM (M ISI «M < «


, u n
inn ifir~ inn mr-
mn oo r«n oo
OO^ 00^ OO^ OO • •




0327d
6-10
03/30/90

-------
€» —
1- C 3
§25
H- W
e o.


0)
,2*
i.
2
•-

1
o
?
2



e^
0* w «>

U VI *
f >«*•
» a.



*^
o -o
c
>» a —
IP
Q. U
e >»—
19 «/> C
^ fi
0*0 —
^
'e •*
C "^
Us
^ iq c
d1

"°i
« «-
U 4*
S  L. •
III
I*J U
E
U
s

V.
vi e
•> —
e.c/1
S? CT
— • — • — w> s/>
SO «D V — Z.Z.
•» Ul tO
^ © ^ i"* i"» 9 B 00
•v v x >, >. x;x ™
voa> •— o — »- •— o


0
Is

0> CL OL GL c"o
•- ^ i- •— 2 S
0 O O O C V
a. a a a £ ra

s »• *• * 3
i« 19 (fl IV k. -O
^ ij ^ O U Q 4J
*" E *•
vi vi vi vl r~ Of
S
c c e vi c L.








^ — — — ^ ^





S 5 S £ K S


(Sl (M » eg



••^ «>^
III 1 1
*n rt um
O NO O *^ ^* C^ ^ O O rt

****«•"«•"

u
isi !
• k. r- Ol
5 » O O
xu»ts e
— ^
o*1
« s.
OO 0 * "~
S! S
i!
o •- ^
if .j!

CO > 'o

O 3
« o>
3 ^ £
u £ S •
c ov, ""§

a. i— ^ •>
VI ID VI C &
o
.- a>

13 3 •
15 o S.
j= a. 3
c * o
•- u ^
Ok
** JJ
"" — 2
"* ~Z "e
***| -, ^ 49
'1 £
JM JC •— J-
5 5 £ "
u. *o O *^
O ^ -
I !S
i lit
^ *- ^

* *~
S *"

!*-
SSt-**
•a A 1 ^*
* *~^
•I"
-il
a * «
• *^
•• 'SSl
£.2
^ » M a.
° • S S
o ft >»<
:• I
Urn
O

c
•I
C4



^
VI
 -o
 Z
£ «
~ e
ttt U
wi C
H c S.
* i I
c u
*
to u
e 9
£ 5 ..
Vt VI
V* *~ **
*l
s
«
i
l*p
o
VI
tt
Q.
vt
9
o
2
^
e
1
Ol
J *
^B
-8
•o
J£
oi a.
3
^v O
*" Ol
Z—
5*0
* A>
. c
3 U
M *
--£
3
ts
£<£
1^
. C
k 3 u
•• k *~
ft t)V-
1 3-f
*• "o "
1 *i
fS *- *J
9 ** C
in ^2
— . •«*.
S ? ^S
- 5 « -
* vi Jt vt
^ s -s
, 0 .0^
i & ?S
» - |5
2 3 1^

«i 3 vt-w
if S So
a a. eno.
5 i 6£
<• A w









































e
w
£
e
VI
'S
c
U*
u
"g
*
o
u
0327d
6-11
03/30/90

-------
 B1anc1f1or1,  1970a.b.c,d,  1971;  Blandflorl  and  SeveM.  1966;  B1anc1f1or1
 and  Rlbacchl,  1962a,b;  B1anc1f1or1  et al., 1963a,b.  1964;  Hllla,  196S; Roe
 et al.,  1967;  Toth,  1969,  1971;  Kelly  et  al.,  1969;  Yamamoto and Welsburger,
 1970;  Bhlde  et  al.,  1976).    The  tumors  were  often  multiple  and  were
 generally  characterized  as   adenomas  and  adenocarclnomas.   Hepatomas and
 hepatocarclnomas were also observed  In the three  strains of mice that were
 treated  orally  with hydrazlne  sulfate  and   developed   lung  tumors  (IARC,
 1973);  these  Include BAlB/c/Cb/Se  mice  (BlandfloM,  1970b,c),  CBA/Cb/Se
 mice  (B1andf1or1,  1970a;  B1andf1or1  et  al.,  1964; Sever 1 and Blandflorl,
 1967,  1968)  and  C3Hb/Cb/Se  mice   (B1anc1f1or1,  1971).   The experimental
 design and results of representative studies are summarized In Tables 6-2 to
 6-8,  and  those most relevant to  quantitative  risk assessment  are discussed
 below.   It  appears  from  the IARC  (1973) review  and  the available English
 papers  that  only  some  of the  mouse studies   employed  multiple  dose  levels
 (Blandflorl,  1970a.b; M111a.  1965). lifetime  administration  or administra-
 tion  1n the drinking water (Toth, 1969, 1972a).
    Toth  (1969)  administered  0.012%  hydrazlne  sulfate In the  drinking  water
 to groups  of  40-50  six-week-old Swiss,  C3H  and  AKR  mice of each  sex for
 life. Groups of  110  Swiss  mice,  30 C3H and  30  AKR  mice  of each sex served as
 untreated controls.  The mice were  either allowed  to die or were sacrificed
when  moribund.   HlstologU  examinations  of the  liver,  spleen,  kidney,  at
 least four lobes of  the  lungs and other  organs  that showed gross pathologic
changes were conducted on  all animals.  As detailed  in  Table 6-4, continuous
 lifetime  treatment  with   0.012%  hydrazlne sulfate  In   the  drinking   water
 produced  pulmonary adenomas  and adenocarclnomas  in 46-50% of  the treated
 Swiss mice,  compared with 9-11%  1n  the  controls.   The average dally  hydra-
 zlne  sulfate consumption  per  Swiss  mouse  was reportedly  0.74 mg   (0.18 mg
hydrazlne) for  the males  and 0.65 mg  (0.16 mg hydrazlne)  for the females.
0327d
6-12
03/30/90

-------
                                   TABLE  6-2

           Incidence of Tumors tn Swiss Mice Treated with >95X Pure
                  Hydrazlne In Drinking Hater for 110 Weeks3
Sex
F
M
H.F

Dose or Exposure**
0.001X
(1 .9 mg hydrazlne/
kg/day)
0.001X
(2.3 mg hydrazlne/
kg/day)
0.0 mg/kg/day

Target
Organ
lung
lymph
lung
lymph
lung
lymph
Tumor Type
adenoma or carcinoma
malignant lymphoma
adenoma or carcinoma
malignant lymphoma
any type
any type
Tumor
Inddencec
(p value)
27/50
(<0.001)
9/50
(<0.001)
24/50
(<0.001)
7/50
(<0.001)
0/220
0/220
(NAJ
                              QUALITY OF  EVIDENCE

Strengths of Study:   Hydrazlne  was  administered  In  the  drinking  water.
                      Water  consumption  values  for males  and  females  were
                      reported.   The durations of  treatment and  study  were
                      appropriate.   Purity  of  the compound  was  reported.
                      Appropriate controls were maintained.

Weaknesses of Study:  Only one treatment level was tested.

Overall Adequacy:     Adequate for qualitative risk assessment


aSource: Toth, 1972a

bDoses  converted  to mg  hydrazlne/kg bw/day,  assuming  mouse body  weight  to
 be 0.03 kg (U.S. EPA. 1986b)

cF1sher Exact Test performed

NA - Not applicable
0327d
6-13
07/26/90

-------
                                   TABLE 6-3

             Incidence of Lung Tumors In Female Swiss nice Treated
                by Gavage with Hydrazlne 1n Distilled Water for
                      40 Weeks and Observed for 60 Weeks3
                    Dose or                  Tumor Incidence
                   Exposure0


                  0.25 mg/day                     6/25c
                 (5 days/week)

                 0.0 rog/kg/day                    8/85


                              QUALITY OF  EVIDENCE

Strengths of Study:   Hydrazlne  was  administered  by  gavage.   Appropriate
                      controls were reported.

Weaknesses of Study:  No  statistics  were calculated  to identify a  signifi-
                      cant  Increase  1n  lung tumor  Incidence.   The  purity of
                      hydrazlne  1s  not  stated.   The  Incidence  of  only lung
                      tumors was reported.  The tumor type Is not specified.

Overall Adequacy:     Limited


aSource:  Roe et al., 1967

DDoses  were  converted to  mg hydrazlne/kg  bw/day,  assuming mice weigh 0.03
 kg (U.S. EPA. 1986b)

c4/4 mice surviving to age 50-60 weeks developed lung tumors.
0327d                               6-14                             03/30/90


-------
.









(0
at
«-
5 ,_
* 5

^™ ^J

Is
UJ ^*
'^ _w
*o "^
^ -^
°0
«j c
JO < —> -
Is £2
3 i*
*~ £ *
^^
(/I ^
Jr i_
i **
3 ii
^5
"'a
S; *"
O>
"o c
c "N
t~t to
•o
^^*
^»















•o
4, _
^ 
O I.


l/> C
a> «-

U W
a> -«-i
Q.V)
00

r- — .
0 2
O O
V V

O^fr
v^
UPI co
CM


u g
§o
.e
c a.
>
1

V)
J^
C 0)
rO (1)
a. 3
VI
a> o
--

- -
nt
^ ^
CM O>
o x,
di1

^9
CM


*
vt
^M»
3l
ex)
%^
a*
u
£


0
0
V



X.
CM


U
Q
C
0)
•o
(9







01
e
3



c
i-
a»
-



^
CM
O
•
0





u_









— — . **— .
•— «M Z Z
0 0
V V

O 0

X. X, X. X.
* CM i— CM
r~
|
•J3
g l_ W g
£ O Of
tc ca.
<1^ &) c
>»-o -o >.
^— m ^o ^™

•o
c
(O
»^
°*
£ i* £
>» g 3 >»

(/I
^^
0)
s
^
c 2

"^**
« 4
X. >s.
O^ Q)
X. X,
W i1

C^5 ^3
CM
— O

*









	 —.
Z Z Z



o o o

X. X, X,
*~ r"
g
e
U
E 0 u
O f O
c a. c
a> E at
•a ^^o
Cfl 1^^ fQ

•o
c
fQ
^™
O)
t_
o> a. g
C E E
3 >> g






2


(0
x^
o>
X.
w

o

o

u_









CD ^^5
^ *~I
o o
V V


O^^
^J
X x,
i— CO
SO


i i
o ^z
£ E"
•o >>
f^ ^™






^
3 >>

^ ^,
I/I
c .*

0.4*
a»
«- CO

^
>
 a.
c E
3 >t

^.
VI
C .tt
ex at
a>
^2.

^
«
•a
x.
O)
x,
i1

o

d
u_
*









CM
.
O
V



21
X,





c
at
•a
c^







O)
c
3



I/I
a>
at
3
O



OX.
0 1*

i^
CO
**^



cc
en
o
x.
at
w
£
at
o •—
*"• o
o o
V •
«— o


*"T •"T
X, X.
•*• in

1
u
k_
0 0
c c
a> at
•o •«
^ (Q

„
C
^
^™
O)
i"
°* E


VI
^^
W
§1

O


*^

-------































*"**
o
u
1
LLJ
CO
N-


































at
u
C
tt)
•a
c


at
Q.
j_

£j
£

^H






^
rO
^7)
b.
O
*•»
0>
»—

it-
ration 0
reatment
3 H-
0




^
b. 0>
O b.
3
Ot It
o o.
O X
LU




X
o>
trt





*^
vi e
o> «-
W b»
Ot **
Q.OO

>,
«-
0> 0>§ uj
I la |
>_ <
LU
U_
I/I ^_
Ot .tt t
0) 0) _J
: $ 1
•— o w
r- 0>



>» >»
•o •«
>s >s,

V. >s
g, g,

O O
o e





^C ^b»







•f-
s
V.

o

jc
o> **
"* a>
•§ *
__
ro .g*

•o — >
a> w>
^j •
^ C 3
^^ 1^ 0
« •** j^
v i °
b. _§ C
° "ro *"
"*"* jt fQ
01 u jj
•^ VI

VI U- f
ft) o U
> ro
£ b»
o» 2 o

^^ ^^
'a ^
b; a>
'•=t?

» « *
2 »- a>
^.i ^»
a> ^
« ^ Q.
"Q. ° •»
** E ^> i,,
»!! »
vi 4) O *~
C ** 0)
^ ro « >
«- *^2 •"
tf% ^O ^_ ^^
« Q. C
-^21
» S £ «
« 32 ^^ 01
^» ^^
** S Q> O
"° ° *» C
fO O
«> -a 3
at 4> a- >v
l_ vi O> r—
^w rO ^3 C
t— A *P O
..
• * ^>
» 13
•O 3
3 *-*

(/>
<*- O
O
v>
v> a>

o> at
c e
at .*
i. ro
•M at
bO 3































C
•essme
vt
ro
^
*~
5
^^
^_
ra
°"
1^
-o
<*»
4-1
ra
1
•Q




• «
3^
y
ra
3
at
•o


^
ro
L.
at
^
o
a>
u
"i

^jjU
<»1

•a
ra
V.
I/I
"5


c
^^

VI
ro
£
C
u
t_
ro
U
O
C
0)
ra

b.
1
c
*~
lecrease
sulfate.
%^
c
N
^O (rt
V ^
*;-o
0 >,
C f
t- ^2
w **
i'
10 ^
0) S
^2 1^
h-**
\









* *
1/1
e

B
B
Q
o
o>
5
ro
V.
•o
^^
.c
i1

o

at
*^
a>

0



V
LM
*
VI
at
VI
o
o


^
5
3 1
01 O
c o.
*• at
C,
^B
*- o at
b. f b.
3 X
C- rO
*" at g
•a ** o
at e
b. >» •«-
•<-• b.
i/> ^ ro
^^ at bt
c -a o
e > at
•Q o *a
ro b. ro
Q.
VI £
32 §
^^ ^*
>»B 9
3° -
^^ ^3 *
?a> vi
v» g
«» "~"Jo o
^^ _ c
^^ .^ ^^ at
^™ «i r^ ^^
^" ^3 fO
* J^ ^^
* 3 2 ,2?
o *" *»
h- 01 C
01 .K ro
c >, c
.. ^01 «^
At tl 3 b.
 X Vi &
ra A o































,2
o
o
°
c
c
(O
.C
VI
VI
•-
^^
pM.
C
ra
u
^"
IV.
0>
V VI
1 at
b. W
o «-
*- E
a at
4^
*j ra
^> Q}
at b.
h- •*<
^. ^»
^"* ••»
ra
x at
LU Ct
e
at -o
^c *^
VI U
«- e
^^ NM
v at


















































at
r*^
.a
rO
U
•»•
a
Q.
ro

^->
O

u

^c
x
0327d
6-16
07/26/90

-------









*v
L*
to
i
c
TO
»•
3
U
e
TO

^,
x:
"5
to

i
>.
«
••*
to
i_
VI
4-i
m
a:

c
n»
s
£
c
fcrt
b.
g
^
'S
ft!
U
c
•o
i















o

ill
• w <9
h- U
e o-



i
*~
!





•jj
TO i-
t— o



I-D-
2^1
Q *O —


tbp
e **
e £ *3T
£| I
^5 « x
3 *- ~~
o





^
js TO
u -o





X
to
CO






•s.
to —
II
— — 	 	 — — 	 jj- —
oo ?? oo 3"imm*

^ r> »— «r m tn «r CM cr» »


1 1 1 1 II
e e e e e e
"5 £ £ "E ^?

O4 O<9 O4 O4 O4U
S S 8 8 S *"
§5 15 l£ 15 Is5
to L. to >- to <- tok tok^











S 5 ff ^» ^B
t— f—





O X A X *A





_ *•• »
533
f) Ol f) 9 O*
^^J0 *^xfo CO^I
-W "9 -I1
S S i/»




K u. u.





Ai •*
C/) C/)
X, Xk
4f U CJ
ii ^
•K U BC
?»
ss s |
*""""" o ~"
V

CM « m
U k. U W
e i e e
|I 1 I
•I S 1 1
« u « «)




en to 01 01
e > e e
3—3 3


U
s
^J
s s s s
^ "~ ^ ^
M
•



! S !





«.
3
CD
O (M V O
" f
C *














1
Uw
o
g
o
ni
t»
1

Ol
1
s
to
to
l/t >
i i

i "i
* £
V ^
*«
 , 1 3
•o er
II I 1



•S"
f 1 i;
— (Aw

 o er
e to
v> •«
vl V <
JC VI
O> to —
c e <9
v •* >-
i 2 $
M So
1
«f
W
1
e

S
trt
m
•o
*^
Ol
to
£
9
to
c

CO 5 ••
>e 5 •"
? * to
^ «s
55".
w 

m § o
e c

T !t a
» 'So
to "
(^ <£•>

e —
»• «
to MX
U TO
3 -O •»
e >» z i-

-------
                                   TABLE 6-6

       Incidence of Tumors  1n Female BALB/c Mice Treated by Gavage with
                   Hydrazlne Sulfate 1n Water for ISO Days3
Sex
c
F
(virgin)


F
(breeder)

F
(gonadectomlzed)

Ooseb
(mg/day)
1.13
(170 mg total)
(38 mg/kg/day)
0
1.13
(38 mg/kg/day)
0
1.13
(38 mg/kg/day)
0
Target
Organ
lung

lung
lung
liver
ovary
lung
liver
ovary
lung
lung
Tumor Type
(p value)
adenoma or carcinoma

adenoma or carcinoma
adenoma or carcinoma
carcinoma
carcinoma
adenoma or carcinoma
carcinoma
carcinoma
adenoma or carcinoma
adenoma or carcinoma
Tumor
Incidence
20/22
(<0.0001)

1/25
(NA)
25/25
(<0.0001)
7/25
(<0.004)
6/25
2/25
(NA)
0/25
(NA)
0/25
(NA)
15/25
(<0.017)
7/26
(NA)
0327d
6-18
07/26/90

-------
                               TABLE  6-6 (cont.)
                              QUALITY OF  EVIDENCE
Strengths of Study:   The Influence  of  ovarian hormones on  the  Induction  of
                      pulmonary  tumors  was demonstrated.  Mice  were treated
                      until moribund.  Appropriate controls were tested.
Weaknesses of Study:  Only one dose was tested.
Overall Adequacy:     Adequate for quantitative risk assessment

aSource:  Blanclflorl, 1970c
bDoses  were  reported 1n  mg hydrazlne  sulfate/day.   They were  converted  to
 mg hydrazlne sulfate/kg  bw/day,  assuming  the  body  weight of mice to be 0.03
 kg (U.S. EPA, 1966b).
cF1sher Exact Test performed
NA = Not applicable
0327d                               6-19                             07/26/90

-------
                                   TABLE  6-7

            Incidence of Liver Carcinoma 1n CBA/Cb/Se Mice Treated
                 by Gavage  with Hydrazlne Sulfate In Hater  for
                            25 Weeks, 6 Days/Week*
Sex
M
F
Dose or Exposure13
(mg/day)
1.13 (38 mg/kg/day)
0.56 (19 mg/kg/day)
0.28 (9 mg/kg/day)
0.14 (4.7 mg/kg/day)
0
1.13 (38 mg/kg/day)
0.56 (19 mg/kg/day)
0.28 (9 mg/kg/day)
0.14 (4.7 mg/kg/day)
0
Duration
of Study
(weeks)
87
78
76
98
100
87
78
76
98
100
Tumor Incidence0
(p- value)
15/25 (<0.0001)
12/25 (<0.0001)
7/25 (<0.085)
1/26 (<0.362)
3/30 (NA)
15/24 (<0.0001)
16/24 (<0.0001)
2/25 (<0.443)
0/25 (<0.55)
1/29 (NA)
Strengths of Study:



Weaknesses of Study:

Overall Adequacy:
        QUALITY  OF  EVIDENCE

The  Induction  of  hepatocarclnoma  by  hydrazlne  was
demonstrated.   Nice were  observed  during the  appro-
priate latency period; several dose levels were used.

Purity of test compound not reported.

Adequate for quantitative risk assessment
aSource:  B1anc1f1or1, 1970a

bDoses  were  converted  to  mg  hydrazlne  sulfate/kg  bw/day,  assuming  mice
 weigh 0.03 kg (U.S. EPA, 1986b).

cF1sher Exact Test performed

NA . Not applicable
0327d
              6-20
07/26/90

-------
                                   TABLE 6-8
           Incidence of Hepatocellular  Carcinomas In Livers of Hale
         Syrian Golden Hamsters Treated with Hydrazlne Sulfate (>99%)
                        in Drinking Hater for 2 Years3
Doseb
(mg/kg/day)
0.0
4.6
8.3
10.3
Tumor Incidence0
(p value)
0/31
0/31
4/34
11/34
(NA)
(NA)
(0.068)
(0.0003)
Strengths of Study:


Weaknesses of Study:
Overall Adequacy:
Comment:
        QUALITY OF  EVIDENCE
The  durations  of  treatment  and   study   were  long.
Appropriate  controls   were   reported.   Methylatlon  of
DNA  guanlne  during the  induction  of  liver  cancer  was
measured.  Multiple doses were used.
Only males were tested.
Adequate for quantitative risk assessment
Hamsters  were  given  hydrazlne  sulfate  In  drinking
water at  concentrations of  170,  340 or 510  ppm.   The
authors calculated the doses of hydrazlne 1n mg/kg/day.
aSource:  Bosan et al., 1987
bDose expressed as hydrazlne (free base)
cF!sher Exact Test performed
NA = Not applicable
0327d
              6-21
07/26/90

-------
 produced  pulmonary  adenomas  and  adenocarclnomas  \n  46-50%  of the  treated
 Swiss  mice,  compared with  9-1IX  In the controls.  The  average dally hydra-
 zlne  sulfate consumption  per  Swiss  mouse  was  reportedly  0.74 mg  (0.18  mg
 hydrazlne)  for  the  males  and  0.65 mg  (0.16  mg hydrazlne) for  the  females.
 Based  upon body weights  provided  by the author, the transformed animal doses
 were  for  males and  females 26 and 23 mg  hydrazlne  sulfate/kg/day, respec-
 tively.   Hydrazlne   sulfate  treatment  did   not   Induce  a  significantly
 Increased  Incidence  of  tumors  at other sites  In the  Swiss  mice or  at  any
 site  In  the C3H or  AKR  mice,  but  the  treatment  substantially decreased  the
 Incidence of mammary gland adenomas In the C3H females.
    Similar  results  were  obtained In  a  similarly designed  study  1n  which
 0.001X hydrazlne 1n  the  drinking  water  was  administered continuously for  the
 Hfespan of  50  male  and 50 female Swiss mice,  which were  6 weeks  old at  the
 beginning  of  treatment  (Toth,  1972a).  The  average  dally   consumption  of
 hydrazme/mouse was  0.069  mg  for  males and 0.056 mg  for  females.  Assuming
 the average  weight of  mice to be  0.03  kg  (U.S.  EPA,  1986b),  the transformed
 animal doses were calculated to be 2.3  and  1.9 mg hydrazIne/kg/day for males
 and  females,  respectively.   The  hydrazlne  treatment  reportedly  Induced
 pulmonary adenomas and adenocarclnomas  In  48-54% of  the mice,  but  elevated
 Incidences of  tumors at  other  sites were not  reported.   However,  concurrent
 controls were not  used In  this study;  the  Incidences  of tumors In untreated
control Swiss mice from the earlier Toth (1969) study served as a reference.
    BlandfloM (1970a)  conducted a  multiple-dose  study  1n  which hydrazlne
                                               *
 sulfate  was  administered  by  gavage  to  groups  of  24-30  eight-week-old
 CBA/Cb/Se mice of each sex at  doses of  0,  0.14, 0.28, 0.56 or 1.13 mg/day, 6
days/week for  25  weeks.    Assuming  that the mice weighed  0.03 kg  (U.S. EPA,
 1986b), the  corresponding  doses  were 0,  4, 8,  16 or  32  mg/kg/day.  Hlsto-


0327d                               6-22                             07/26/90

-------
 logical  examination of  the  livers,  lungs, unspecified  endocrine  glands and
 other  tissues suspected  of  having lesions were  conducted on  all  mice when
 moribund  or at  the time of  natural  death.  Multiple  pulmonary  tumors were
 reportedly  present In  "many"  of  the  treated  mice, but  Incidences  were not
 reported  because the purpose  of  this  study was  to describe hepatic tumors.
 Hepatic   tumors,   classified   as   very  vascularlzed  hepatocardnomas,  were
 Induced   1n  a  dose-related   manner  In  both  sexes  (see  Table  6-6);  lung
 metastases  were  observed 1n  some of  the high-dose  (37.7 mg/kg)  mice.   A
 multiple-dose  study that was  not available  for   Independent  review showed
 that  similar  gavage  administration of  hydrazlne  sulfate  also resulted  in
 dose-dependent  Induction of  pulmonary  tumors  In  the same  strain  of  mice
 (B1anc1f1or1,  1970b).
    Sever 1  and  Blanclflorl   (1968)  administered  dally  doses  of  hydrazlne
 sulfate  at  it and 12  mg/day  to 14 male  and  18 female  Cb/Se  rats, respec-
 tively, by  gavage from  the age of 8 weeks for 68 weeks.  Assuming an average
 body weight  of 0.35 kg  for  rats (U.S.  EPA, 1986b), these doses correspond to
 51  and  34 mg  hydrazlne  sulfate/kg/day for males  and  females,  respectively.
 Untreated groups  of 28  male  and 22 female rats were  used  as  controls.  The
 liver,  lungs  and other  organs  that showed  macroscopic  lesions  were examined
 hlstolog1ca11y  at  the   time  of  natural  death.   Lung  tumors  (adenomas  or
 adenocarclnomas)  were  found  In  3/14  males and  1n 5/18 females  after  109
 weeks  but  in  none of  the  untreated  controls.   Liver tumors  (hepatic cell
 carcinomas  or  spindle  cell carcinomas)  occurred  In 4/13 treated  male rats,
 0/13  treated females and In  none of  the untreated  controls.   Spontaneous
 liver  tumors  had never  been  observed  in Cb  rats maintained  In  the same
 laboratory  during the previous 14 years.  Stelnhoff  and Nohr  (1968), how-
 ever, reported only a weak carcinogenic  effect  of hydrazlne In Ulstar rats.


0327d                               6-23                             07/26/90

-------
 Hydrazlne  was  administered in drinking water  In  concentrations  of 0, 2,  10
 and  50  mg/i  until   the  spontaneous  death of  the  rats.   Using  U.S.   EPA
 values  for the  body  weights  of rats  (0.35 kg)  and dally water  consumption
 (0.049  i/day),  these  doses  are  approximately equivalent  to 0,  0.26,   1.4
 and  7.0  mg hydrazlne/kg/day.   Each  group consisted  of  50 males  and  50
 females.   Hostly  benign   liver  cell  tumors  were  found  with  the  highest
 concentration used.
    Administration  of hydrazlne  sulfate   to  Syrian golden  hamsters  In  the
 drinking water  at a concentration  of  0.012% (average dose, 2.3 mg/day)  for
 life  (Toth,  1972b) or by gavage at doses of 2.8 mg/day  (10  applications  In
 20 weeks)  or  3.0  mg/day  (60  applications 1n 15 weeks)  (B1anc1f1or1,  1970c)
 did  not produce  significant  Increases   In  the  Incidence  of  tumors after
 lifetime observation.   Assuming the average  body weight of  hamsters to  be
 0.14 kg  (U.S.  EPA. 1986b), these three doses  correspond to 16,  14 or 12 mg
 hydrazlne  sulfate/kg/day.   Bosan et al.  (1987)  reported an  Increased  Inci-
 dence of hepatocellular carcinomas  In  Syrian golden hamsters  after treatment
with 170,  340  or  510  pom hydrazlne sulfate 1n drinking water [4.6, 8.3  or
 10.3 mg  hydrazlne (free  base)/kg/day,  as  calculated  by the authors] for  2
 years.
 6.2.3.   Other   Relevant  Information.    A  single  Intraperltoneal  dose  of
 hydrazlne   sulfate  to  male   CBA   mice,  together  with   [14C]fornate   or
 l-[methy1-"C]meth1on1ne  as   a   source  of  14C,   produced   [l4C]7-methyl-
 guanlne in liver  DNA and  RNA  (Qulntero-Rulz et al., 1981).   No methylguanlne
was observed In controls  treated only  with the source of "C.  The  alkyla-
 tlon of  nucleic  acids  suggests  a  possible  mechanism of hydrazlne  carclno-
genldty.  The  methylatlon  of DNA  guanlne  In  the liver, kidney and  lung of
hamsters after  oral  treatment with  hydrazlne  was  also reported by  Bosan et
al. (1987).  The study 1s  described 1n  Section  6.2.2.
0327d
6-24
07/26/90

-------
     No  Indication  of  a  carcinogenic  effect  of  hydrazlne  was  found  after
 subcutaneous  Injection  of  0.25-5  mg/kg of  hydrazlne once  a week  for  2.5
 years  Into groups  of  50 male  and 50 female  Sprague-Dawley  rats (Stelnhoff
 and  Hohr,  1988).   Negative  results  were  also  found  after  Intratracheal
 administration  of 0.25-5 mg/kg  of hydrazlne  1n Sprague-Dawley  rats  once  a
 week for  2.5 years.
 6.3.   GENOTOXICITY
     Hydrazlne was generally positive  In  reverse mutation tests In Salmonella
 typ_h_Hnur_1um  (Herbold and  Buselmaler,  1976;  Rowland and Severn, 1981;  Wade et
 al..  1981) and Escherlchla coll  (von  Wright, 1981; Noda  et  al., 1986) with
 or  without activation, and In phage  tests  and a ONA  damage  test 1n  £.. coll
 (Helnemann,  1971;  Green,  1981;  von  Wright,  1981).   Results  were  also
 positive  in a  forward  mutation   test  In  several  strains of  Saccharomyces
 cerevlslae  (Lemontt,   1978; NcDougall  and  lemontt,  1979; Lemontt and  Lair,
 1982).    Results   1n   Drosophlla   melanogaster  were  positive  for   somatic
 mutations  and  mixed In  the sex-linked  recessive  lethal  test  (Shukla.  1972;
 Vljaykumar and Lain, 1979; Yoon et al., 1985).
     Results  of  Jni vUro  tests  In mammalian sytems  were  generally positive,
 Including  sister  chromatld  exchanges  1n  Chinese hamster  ovary cells  (HacRae
 and  Stlch, 1979;  Perry  and  Thomson,  1981),  DNA  damage  1n  rat  hepatocytes
 (S1na et  al., 1983), and  unscheduled  DNA synthesis 1n HeLa cells (Martin and
 McDermld,  1981}   and  human flbroblasts   (Agrelo and Amos, 1981).   Negative
 results  were reported j£  vivo  1n  the  mlcronucleus  test   (Tsuchlmoto  and
 Natter, 1981) and dominant lethal  test (Epstein et al.. 1972)  In mice.
 6.4.   DEVELOPMENTAL TOXICITY
    Pertinent data  regarding  the  teratogenlclty of  hydrazlne  In  animals  are
 few, and  no human studies were   located.   No Inhalation studies  regarding


0327d                               6-25                             07/26/90

-------
u
e
4)
«*»
ac

e


41
|
ac
OI
*«, 2f
e *• *
^ 
'I I
* c : »
«- « M
*j ••* •- *
S £ *•
S *- Sfe
>» e
«•» o
«- <_>
M
O
o *••
» I*
aC

|
w
i
•
o»
4.
O
*
U
•5


V*
0327d
•o - C i*- ^ 5 *
d !•> *V 91 GT , g > •w» g
(A 1
S« 4i * e
""' — £ 2 "Sii ° i
"'a— v 3^ £>o •— "3
in  O^AIOMC
U1 ••-> L. a «<«- 4. •- 3 3 41
*- vi ns -o <•" •o M «-• 4> o e
e^oiu » MO, ^ •- c w o 4) u
"~ i * 'S w . 'W'^**<1 '
>O.('O • 5"* • — tSi^Zi
^io«i 5 MOW M 4t v ••— 3 V
«-> 41 L. w 4.  <» •* •( O tl
"ui IS *" •« "*" ^ 1) •— Vwi« M
££S»- 5 s?uS iS^aSS *

*. | 4. 4- * *
^h ^^ ^K ^K O
en «/> CA v> u ae
4>
M
t> •>
si; si:
m •— i— •—
L. a. o.
0 o^. o^. S
«M S » «- » _•
— 1 *~o -o o15
•s. «o »- e &~ •—
- w O wn 10 O a.
(M • (M (M *fM «— *V *
^•» ^^ 1 9 l^
o~ *o o e 1* o

S S S S S
1 II 1
o o e o
1 Is I
£ 5 5 5 S
41 41 4> 41
— C **C •* C "6 "-•
«o i*5 +o *o o^
* !. IB. I. 1
5 tl 1* il** 1< £
5 • *o ^P 3 12 ^_ 2152 TSi ^^ S «^ u
o ^™ F* n ^ ft ^s ^i^^ ^^ 52 Sc w
e
o
(«
1
41
M
4.
•I
>
41
ac
6-26
o> * •—
*- «« S
e c « -ooo «
D ••
L_ *3 C > "~* ll C "3
i MO -- C  •-•- a ~ o.
M 4)MM 4>O>OM tl
O C 41 C £xCk4l C
3 IV 4. 4> *» •*» £ u
u -o «- v> e^-Bio*' -o
«M 5,2k 5I*£fl £•
M 4> 3 •i8ik"4l
t<- -0 4. 0 <«M lw -0
^ ^j ' *- ^o*^e _*»
M * tn M^ Z^-52^ tJ
4.«- H- -o 'nj « 'S • Ji « I—

* * * *
B
u *> en
ac (/iv>
1
1 J. 40
* 2 7. 31

S S S
r i
i i
s s
O (J *•*
^ i- 4»
|| || |
S *
« * U a < ti
> *" «\J -O «M 
-------
flU
u
£ S-
k. • IB CO
41 — .OS
t» e> e 5 "~
" i^ |_ ||
O  — X— CDI/>

I — C
4> O 19 41 —

iZ i ">• £ 5 —
'£ "" "° 2 "S 5 ^
41 4> »- 4i "O C C C
I e o e >, >,IB
I f C — f •O VI
5 M M — 41 *
k. IB k. e z N ••
13 * •O J3 K ca C <
.c 41 f 41 — e a
•oeoi -o «- Sesi""IZ*
41 O — 41k. V »• C <
i— w. k. i— u t~ ew Hu
41 * * i
QC
e
> VI 41 41
— »• e e
•*• «/> oe O O
w zee
e
o
— 41
IB VI
k. 0 X -
-o 1 S
41 k. O 0>
u e CM a
e
O k. O
u O O

o vo oe
— Al *
'kt X
3 —
a. ec ae ae


e
o

— »* **
IB VI VI
W 4) 4)

0. 41 «
a. a -o
« a ae a

g
•£ <« X*
0> "i S
k. it> r* vi
0 — " — f e
— — — a 41 e

S 1^ i
VI B ** O
vi »B a k
« -t ! a.

asxs oC
I— C r~  fo ^ 
B o o o k. j< «cn
COCE** 3 — TO r—
vwcSiiv -e — c «< .
— 1 i _J — 1 _1 W> » r« — <
•o «
41 O 41
>> >| M - •*• k. O
•— e 4i a o •—
3 — — ""l! lc*o
(fl — — 414! u— •—
*• — « > ex S^k,
luu «"^ -a "vi o
41 " i o
»  e o " e •« <« .
j o « "It » *•
--•04ie el e"4»
•| vi4ikiO 4t& «— vivi
V|-O"<- EO M4IB-O
CX CX VI > 4I> -0 vi VI VI
X 41 O — k.41 >. - -o z a i- — <
+ * +
41
e
o « « •
e m m i




X X 3
X


^n -5 —
e t) v
41 41 41
CX 4) 41

a

— > > •
"J to IB


IA kr
e 4t
4i le k. vi
W k. 41 IB
> 41 *• IV" 0
E IB VI —VI O
5 — — IB w c x
k. V> — ,C O 1 IB 1
IB— IB aoe — c
^ > k. oeo v o
U 41 41 viiBOl ioi
U k. > O •— 41 41
M U VI C3 • O OlO

e c
O 0
i 1
i i

X) W
1 |

0 O
b. U}

M »


IB 0* "0 —
>B 41 VI 41 -
— k. > IB f
Sem oi -x ae u
a CD o> u u —
E o en o i 41 41 O

Q.IB IB IB TJ -0
C fc — >. 41
J*i E >> ••
S vi f 41 £ 41 41
•a -o e • « — e
-41 41 O(M 4lk.O
- -O *. CX VI — ^ °-
|— « a>4-> «f4>
/5 u i— ae * •— w k.
* t * *
41 «
c e
c « o o
E z e e



1^1^ i *
E cx— ex"u <-> o
•O 41 kO —
— o 4i o —» < m «
9 o 410 e <— • n
^ u- kf> •- • O •
3 (M —CM — . O — 10
S ?i IS


4, 4,
k. k.
k. a a
o e •> •"

0) oi— a a
c e ** u w
— — • u
O -O 41 — —
841 ^^ — —
41 e 41 41
te Ik 1— U W
VI
k. k. 4i k.
U 4l u 4)
W VI *" £
o o — S —
ex e ui 4i
IB ' 19 -J 41 u
|i O "i 41 S ><
« 11;
slca cil e u e

— c -o
2 $. -
It IB 1
— •WO
^41 E Je
M > u 41
e ^ ^ 01
T SJ 3—2
X U k. VI U
41 41 O — X
M k. u.  
-------























•"""*
i
u
01
1

























tl
c
Ink








^
e

^


41
i/i
|
oe
e


*"
§
•» 4)
(V VI
u O
e
1°
„
"US!?
5 *""





c
o
2

I


5
c
J5
o
u
1




5"

»
ll'
o
II
j2
^ ^
i," 5 i
— 41 l« 01
«« l. — C
a » i 19

••* v> ^
S— • e •»
VI V W
i_ »• e o

£ 15 L. tJ
4> D*« e >>
»- «> »•• C M

"c
* 1
Wl U

«n
?i

1
§
o

QC





a
a
u

w


•
i-
VI
41 »>
e b.
u o

•o
1
l»
U 4>
o>
VI u
•- X


i
.
i


41
19
a
VI

1
M

^
I
>—


1



g

of
ss
~-

s





9
*a
u
1


«
*
u
f~
i
e»
a
u

Ol

1
i

;
^
41
£S


4^
U»
5f
^

X
e
e
£



*



S

o
€•»
oo


OB





a
3
w

u


s
«*
>»
s
!
l


li
o "~
^1


41
5
"a
VI

1

^
^
VI
41


*



?

1
II
0?

S





1.
a
a
u

u

VI
VI
r~
€
k.
A
1^.
C
1





•o
c
+* ^
i^.
f 41
a «*


«
3
'a
VI

1
M
k.
^
i
VI
41


1



S

oo.

^?

S


trt
t i^.
••» i g
t» «r,e


"* S c ti
II£I



s
*
•
o «
U VI

VI
VI
a
S
e
e
K

 « u
^ «4
e_c
5fl


1



2

I
(V
e
(V

s

1 VI
"u e
41 —
&-M
b 41
** ^^
6 6

|I
VI ~

41
•
W%
3
i
ec
o

„
IV
o
c
E
I-
l±

























i
pw
o
u
•
1
w
•
e
4>
v»
5

*
O
•g

g
IK
M
«
a
4)
VI
2
g
M
*
£
M
3
5
1C
41
U
e
<9
+*
VI









































•o
41
+*
k
£
e
e
*
at
«"
O
|
IV
d-l
e
a:
H
0327d
6-28
                                                                     07/26/90

-------
 teratogenU  effects  from  hydrazlne exposure  were  located  1n  the available
 literature cited  In  Appendix A.
     Schiller  et  al.  (1979) examined the  effect  of  a single 260 mg/kg gavage
 dose of hydrazlne  on  day 12  of  gestation on the  development  of Intestinal
 brush  border  enzymes  1n  Syrian   golden  hamsters.   Exposure   to  hydrazlne
 significantly  (p<0.05)  reduced neonatal  (3-  to  4-day-old) lactase activity,
 Increased  neonatal  and  postnatal  (24- to 25-day-old)  alkaline phosphatase
 activity,  and elevated  postnatal  but  decreased young  adult  (53- to  60-day-
 old)  sucrase  activity.   The number  of offspring assayed  was  not specified,
 but  the treatment and  control groups  consisted of 24  mated  hamsters  each.
 Head  examinations of  the  treated  neonates  revealed normal  palate  develop-
 ment, but these data were not  reported quantitatively.
     Lee  and  Aleyasslne  (1970)   Injected  hydrazlne  subcutaneously  Into  12
 pregnant Wlstar rats at  a  dose of 6 mg/kg/day on days 11-21 of gestation.  A
 group  of 15  pregnant  rats  served as  vehicle  (saline)  controls.   Maternal
 deaths  occurred   In  two of  the  treated  and  none  of  the control rats,  but
 additional indices of maternal toxUlty were  not evaluated.  Fetotoxlclty In
 the  treated  group was  Indicated  by  a reduced  ratio  of  fetal  survivors  to
 Implantation  sites  (37% In  treated vs.  79%  1n controls)  and  significantly
 (p<0.001)  reduced fetal weight.   Gross  malformations  were not  observed  In
 the  fetuses  of   the hydrazlne-treated  rats,   but  generalized  edema  and,
 occasionally,  petechlal hemorrhages  were  present.  Neonatal   survival  was
 determined In  additional groups of  12 treated and 15  control  rats;  none of
 the  hydrazlne-treated rats gave birth  to  newborns  that  survived the  first 24
 hours, but newborns from 12 of the control rats survived.
    The  results   of  embryotox1c1ty/teratogen1dty  studies conducted by  the
 Air  Force  Aerospace Medical  Research  Laboratory  are available  In  abstract
0327d
6-29
07/26/90

-------
 form  (Lyng et al., 1980;  Keller  et al., 1982).   In  a study with F344  rats
 (Keller  et al.,  1982), hydrazlne was  Intraperltoneally Injected at  unspeci-
 fied  doses  <10  ing/kg on  days  6-15  of  gestation.   Dose-related   embryo-
 lethality  and maternal  toxlclty  (not  described)  were observed at  the  two
 highest doses.  Injection  of  10 rag/kg  hydrazlne  on gestation days  7-9,  10-12
 or  13-15   Indicated that  the most  susceptible  prenatal  period  was  on  days
 7-9; embryolethalUy and an  Increased  Incidence  of anomalies (not  detailed).
 but  no  major  malformations,  were   observed   In  this   group.    Increased
 perinatal  mortality was also  noted  1n  the offspring of rats  Injected with 10
 mg/kg hydrazlne on gestation  days 7-9,  but  neonatal developmental  parameters
 (I.e., weight gain,  ear detachment,  Incisor  eruption, eye  opening,  surface
 righting,  cliff  avoidance,  forward  motion  or  swimming  ability)  were  not
 adversely  affected.  Percutaneous treatment with 50 mg/kg  hydrazlne  on  day 9
 of gestation  reportedly produced a  high Incidence  of  embryolethalUy 1n F344
 rats, but  similar  treatment  with  5 mg/kg was  not embryolethal;  additional
 data regarding this experiment were not reported 1n the abstract.
    Intraperltoneal Injection of hydrazlne at doses of 4,  12 or  20 mg/kg/day
 on days 6-9  of gestation had no significant effect on the number  of Implan-
 tations per  female, mean  number  of viable fetuses  per Utter  or mean  number
 of resorptlons per  Utter  1n ICR mice, but  similar treatment with  30  or  40
mg/kg hydraz1ne/day  was fetotoxlc  {Lyng et  al.,   1980).  Maternal  toxlclty
was Indicated at doses >4  mg/kg/day by reduced  weight gain during  the Injec-
 tion period  (12 and 20 mg/kg/day) and  mortality  (4/21 died at 40 mg/kg/day).
 Fetal soft tissue  (e.g., exencephaly  and hydronephrosls)  and skeletal  (e.g.,
 supernumerary Mbs) anomalies occurred  1n all groups  treated with  <40 mg/kg/
 day.  Additional  data regarding this study  were not reported In the abstract.
0327d                               6-30                             07/26/90

-------
 6.5.    OTHER  REPRODUCTIVE  EFFECTS
    Seller   (1977}   evaluated  several  chemical  mutagens  and  carcinogens
 Including  hydrazlne  for   their  effects on  testlcular DMA  synthesis.   Hale
 mice  weighing  between  23 and  28 g  received  a  single  oral  dose of  200 mg
 hydrazlne/kg.    Hydrazlne  administration   Inhibited  mouse  testlcular  ONA
 synthesis,   similarly  to  other  mutagens  and  carcinogens;  [*H]thym1d1ne
 Incorporation was 72.4X of control (p<0.05).
    Sotomayor   et  al.  (1982)  measured the  occurrence  of  unscheduled  DNA
 synthesis  In melotlc  and postmelotlc  germ-cell  stages of  male  (101xC3H)F1
 mice  after  IntrapeMtoneal  Injection  of  10,  20,  40, 80  or 120 mg  hydra-
 zlne/kg.   Sixteen  days  after  Injection,  sperm  heads from  the caudal  and
 caput  epldldymls were  collected.   The sperm  heads  were  then  assayed  for
 unscheduled  DNA  synthesis  by  Incorporation   of  [»H]thym1d1ne,   Hydrazlne
 did  not  significantly  increase  unscheduled   DNA   synthesis at  any  dose.
 Because hydrazlae**  known to damage DNA,  thus stimulating DNA repair mecha-
 nisms,  Sotomayor  et al.  (1982)  concluded  that either  very little  hydrazlne
 reached  the  spermatogenlc cells,  or  that  the  DNA  repair  enzymes do  not
 recognize hydrazlne-lnduced damage.
    Uyrobek  et  al.  (1981) evaluated  the  capacity of  hydrazlne to  Induce
 morphologically abnormal  sperm In male B6C3F1/CRL mice at  doses  between 0.9
 and 400 mg/kg.   No  Increase  In  the  number  of  abnormal sperm was  observed In
 hydrazlne-treated mice  at any  dose  compared  with control  mice  treated with
 the distilled water vehicle only.
 6.6.   SUMMARY
    Hydrazlne lethality  was  dose-related  1n  female mice exposed by Inhala-
 tion  continuously to  0.26 or  1.3 mg/ma,   or  Intermittently  to  1.3 or  6.5
 mg/m>,  for  6 months;  the  percentages of  mortality were  2.5.  7.5, 35  and
0327d                               6-31                             07/26/90

-------
 55%,  respectively  (Haun and  Klnkead,  1973).   Hepatotoxldty may  have  been
 the  cause  of  death.   Comstock et al.  (1954) reported high levels of mortal-
 ity  1n  rats,  mice,  guinea  pigs and dogs exposed to  18  mg/m3  for <6 months.
 Jacobson  et  al.  (1955) reported  4-hour  Inhalation LC.   values  for  mice
 (330 mg/m9) and rats (747 mg/m3).
    The  carcinogenic  potential  of  hydrazlne was  assessed In  an extensive
 study  of  Inhalation  exposure  in  F344  male  and  female  rats,  male  Syrian
 golden hamsters, male  and  female C578B1/6  mice, and male and female beagle
 dogs (Carter  et al.,  1981;  MacEwen  et  al., 1981; Vernot et al.. 1985).   The
 animals were exposed to hydrazlne vapor at  concentrations of 0.07. 0.33, 1.3
 and  6.5  mg/m3 for  rats and  hamsters,  0.07,  0.33  and  1.3 mg/m3  for  mice.
 and  0.33 and  1.3  mg/m* for  dogs  over  a  12-month  period.  At  $.5  mg/m3.
 the  Incidence  of  nasal benign  (adenomatous polyps)  and malignant  (squamous
cell carcinoma) tumors  Increased 1n rats,  and  the  Incidence of nasal polyps
and  thyroid  adenocardnomas  increased  In  hamsters.   A  significant Increase
 1n  pulmonary  adenomas  was  observed   In  mice  exposed  to  1.3  mg/m3.   No
carcinogenic effect  was found  in the dogs.
    Oral  exposure to  hydrazlne  Increased  the Incidence  of pulmonary tumors
 in  different   strains  of mice   (IARC,   1973;  Blandflorl,  1969, 1970b,c,d,
 1971;  BlanclfloM   and   Seven.  1966;   Blandflorl  and  Rlbacchl,  1962a,b;
Blandflorl et al..  1963a.b,  1964; Hllla, 1965;  Roe  et  al.,  1967;  Toth,
 1969, 1971; Kelly et al.. 1969;  Yamamoto and HeIsburger, 1970; Bhlde et al.,
1976).    Nice  generally developed  multiple  adenomas  and adenocardnomas.
Three strains  of  mice  also developed  hepatomas  and hepatocardnomas (IARC,
 1973).    In  contrast,  a decreased  Incidence of  mammary gland  adenomas was
observed  1n  female  C3H  mice  that  received 0.65 mg hydrazlne  dally  In the
drinking  water (Toth.  1969).   Blandflorl  (1970c)  administered  hydrazlne
0327d
6-32
07/26/90

-------
 sulfate  by gavage  to 8-week-old CBA/Cb/Se mice  at  doses of  0,  0.14. 0.28,
 0.56  or  1.13  nig/day.  A dose-related  Increase  In  vascularlzed hepatocard-
 nomas  was  observed  In  both sexes.   Lung  metastases were also  found  at the
 highest  dose tested.
    Sever!  and  Blandflorl  (1968)  reported  that lung  tumors  (adenomas and
 adenocardnomas)  were found In 3/14  male  and  5/18  female Cb/Se rats exposed
 from  the age  of 8 weeks  for 68 weeks to  dally oral  hydrazlne doses of 18 mg
 for males  and 12 mg for females.  Hepatic carcinomas  were  also observed In
 4/13  males  and 1n 0/18  females.  No  spontaneous  hepatic carcinomas had been
 observed previously  In   the  Cb   rat  colony maintained  In  this  laboratory.
 Stelnhoff and  Mohr  (1988) concluded  that  hydrazlne  was  a weak carcinogen In
 Wlstar  rats  that received  0,  2, 10  or 50 mg  hydrazlne/t  until spontaneous
 death.   Benign liver cell  tumors were obwrvwd  only at the highest concen-
 tration  tested.
    Significant  Increases In tumor incident*  were  not   found  1n  two studies
 of  Syrian  golden  hamsters  that  received  2.3  mg/day  in drinking  water  for
 life  (Toth,  1972b)  or   gavage   doses  of  2.8-3.0   mg/day   for  15-20  weeks
 {Blandflorl,  1970c).  Bosan et  al.  (1987),  however,  reported  an  Increased
 Incidence  of  hepatocellular  carcinomas  In  Syrian  golden  hamsters  that
 received 4.6, 8.3 or  10.3 mg hydrazlne/kg/day for 2  years.
    Subcutaneous  Injection  or   Intratracheal   instillation  of  0.25-5  mg
 hydraz1ne/kg once/week  for  2.5 years  had  no  carcinogenic effect  In male or
 female Sprague-Oawley rats (Stelnhoff and Mohr, 1988).
    Hydrazlne  Is genotoxlc  In  prokaryotes,  lower   eukaryotes,  insects  and
 mammals.  Hydrazlne  caused  DMA damage In  phage and  E..  coll  (Helnemann, 1971;
 Von Wright,  1981; Green, 1981)  and  1n animal  cells in vitro  (S1na et al.,
 1983), as  well as  unscheduled  DNA synthesis  In human  flbroblasts  and HeLa
0327
-------
 cells  in  vitro  (Agrelo and  Amos,  1981; Martin  and McDermld, 1981).   Gene
 mutations  were  observed  1n  Salmonella  (Wade  et  al..   1981;  Anderson  and
 Styles.  1978;  HerboId  and  Buselmaler,  1976; Rowland  and Severn,  1981),  E..
 coll  and  yeasts  (Noda  et   al.,  1986;  Von Wright,  1981;  Lemontt,  1978;
 NcDougall  and  Lemontt,  1979).   Hydrazlne  Induced  somatic  mutations  In
 Drosophlla (Shukla,  1972;  Vljaykumar  and Oa1n,  1979) and  mouse L5178Y cells
 hi  vitro (Rogers and  Back,  1981).   No  effect  of hydrazlne was  observed in
 the  In  vivo  mlcronucleus  test  or  the  dominant  lethal  assay  In  mice
 (Tsuchlmoto and Hatter,  1981; Epstein et al., 1972).
    Hydrazlne-lnduced   systemic   toxklty   after   Inhalation  exposure   1s
 observed  primarily  In   the  liver,  lungs  and  blood.   Dogs  exposed  to  6.6
mg/m*  Intermittently  or  1.3  mg/m'  continuously  for   6  months  suffered
 decreased  red  blood cell  counts,  hemoglobin concentration  and hematocrlts,
and  increased  erythrocyte  fragility (Haun  and  Klnkead,  1973).   Under  the
 same exposure protocol,  fatty  liver changes  In  mice and  moderate fat accumu-
 lation In  the "liver  of  rhesus monkeys were  observed.  Similarly,  Cornstock et
al.  (1954)  found  fatty  liver  changes  1n  beagle  dogs  exposed  to 18  mg
hydrazlne/m9 for  <6 months.   Cornstock  et al. (1952) reported  emphysema  and
 Interstitial  pneumonltls  1n  rats  and  emphysema  and atelectasls  1n  dogs
exposed  to  6 mg  hydrazlne/m* for 31 weeks.  Chronic Inflammation,  atelec-
 tasls and  lymphold  hyperplasla were observed 1n  guinea pigs  exposed to 3-6
mg/m»  for  2 weeks  followed  by  8 weeks  at  4-8  mg/m* (Weatherby  and Yard,
1955).   In  the   sane   study,  pathological   changes  noted  In  mongrel  dogs
exposed  to  3-6 ing/a*  Included central-zone fatty degeneration  and necrosis
of  the  livers and  accumulation of  bile pigment.   Capillary damage  In  the
kidney and lung atelectasls were also observed (Weatherby and Yard, 1955).
0327d                               6-34                             07/26/90

-------
     MacEwen  et  al.  (1981)  reported that hydrazlne exposure caused aspermato-
 genests  or  hypospermatogenesls  in Syrian  golden hamsters.  MacEwen  et  al.
 (1981) also  found  that  female rats suffered lesions Including ovary atrophy,
 salplngHls  and  endometrltis when  exposed  to  6.6  mg  hydrazlne/m3  for  1
 year.
     Systemic  toxlclty after  oral  exposure  to hydrazlne 1s similar to Inhala-
 tion  exposure.   B1anc1f1or1  (1970a)   administered  hydrazlne  by gavage  to
 Syrian golden hamsters  (2.8-3.0  mg/hamster  for 15-20  weeks;  assuming  a  body
 weight  of 0.14  kg,  this  Is equivalent  to -20  mg/kg)  and  observed  severe
 liver  lesions Including cirrhosis, bile duct proliferation, pressure atrophy
 and  hepatocyte degeneration.   In contrast, male albino rats  that  received
 between  15 and 25 mg  hydrazlne/kg/day for  3  or  4 weeks  suffered  no  patho-
 logical  changes of  heart,  lung,  liver,  spleen, stomach,  small  Vnte$t1n<,
 kidney, adrenal, pancreas or  testes (Weatherby and Yard, 1955).
    Occupational  exposures   to   hydrazlne  In  gold-plating  (Wrarvgsjo   and
 Martensson,  1986)  and  soldering  work   (Frost  and HJorth,  1959)  resulted  In
 contact  dermatitis  and  eczema,  respectively.   Workers  recovered completely
 after exposure was discontinued.
    Hydrazlne  does  not  appear  to be  teratogenlc,  although  U 1s  clearly
 embryo- and  fetotoxlc at levels  associated  with  maternal  toxlclty.   Lee  and
 Aleyasslne (1970) Injected  pregnant rats with  8 mg hydraz1ne/kg/day subcuta-
 neously  on gestation days  11-21.   None of  the  hydrazlne-treated  rats  gave
 birth  to  newborns  that survived  the  first 24  hours,  while  newborns  from
 untreated  control  rats  survived.  Keller  et al.  (1982)  determined  that  the
 most  susceptible  prenatal  period regarding   embryolethality   1n  rats  was
 gestation  days  7-9.    Lyng  et  al.   (1980)   administered  IntraperHoneal
0327d
6-35
07/26/90

-------
 Injections  of 4, 12.  20,  30 or  40  mg hydrazlne/kg and  found  that maternal
 toxldty  was  also Indicated by reduced weight  gain (at  12 and 20 mg/lcg) and
maternal  death (4/21 rats died  1n the 40 rag/kg group).
0327d                               6-36                              07/26/90

-------
                     7.   EXISTING GUIDELINES AND STANDARDS
7.1.   HUNAN
    The  ACGIH  (1989)  has  set  a TLV-TWA  for  hydrazlne at  0.1  ppm (0.13
mg/m3}  for  occupational  exposure  during   an  8-hour  workday   and  40-hour
workweek.  ACGIH  has  not recommended a TLV-STEL  for  hydrazlne (ACGIH, 1989)
but has  designated  hydrazlne as a "suspected  human  carcinogen"  and given It
a  "skin"  notation,  Indicating  that  cutaneous   absorption  may  contribute
significantly  to  total  absorption.  ACGIH  (1989)  Is  considering  a reduction
In  the TLV-THA  to  0.01  ppm.   NIOSH  (1978)  recommended that  occupational
exposure  to hydrazlne be limited to  a 2-hour celling level of 0.03 ppm (0.04
mg/m3).   OSHA (1989) has  directed that  the  final-rule PEL  for  exposure to
hydrazlne  be  set  at a  TWA  concentration of 0.1  ppm  (0.13 mg/m3).  Further-
more,  OSHA (1989)  has  given hydrazlne  a  "skin designation,"  Indicating that
dermal  absorption   of   hydrazlne may   contribute  significantly  to  total
exposure.
7.2.   AQUATIC
    Guidelines  and  standards  to protect   aquatic   life  from   exposure  to
hydrazlne were not located In the available literature cited In Appendix A.
0328d                               7-1                              03/28/90

-------

-------
                              8.  RISK ASSESSMENT
 8.1.    CARCINOGENICITY
 8.1.1.    Inhalation.   MacEwen  et  al.   (1981)  Investigated  the  oncogen1c
 effects  of  a  12-roonth  Inhalation exposure  to hydrazlne  sulfate  In  mice,
 rats,  hamsters  and  dogs.   Statistically  significant   Increases   In  tumor
 Incidence  were observed  In female mice exposed to 1 ppm (lung adenoma), male
 and  female rats  exposed  to 1  or 5 ppm (nasal cavity adenoma/adenocardnoma),
 male  rats  exposed  to   5  ppm  (thyroid  adenocardnoma)  and  Syrian  Golden
 hamsters   exposed  to  5   ppm   (nasal  cavity  polyp)  (see  Table  6-1).   The
 Increases  In tumor  Incidence  and polyp  formation  were dose-related  In  all
 cases.  No Increase  In tumor Incidence was observed In dogs.
    This  study  was  well  designed and  comprehensive;  several  species  were
 exposed  to hydrazlne sulfate  at  <4 dose  levels,  hlstopathologUal  examina-
 tion of  the animals  Included 44  tissues  and  organs,  the  exposure period was
 long,  the  follow-up observation  period was  24-50 months,  and  appropriate
 controls and statistics were reported.
 8.1.2.   Oral.   B1anc1f1or1   (1970a)   administered  hydrazlne   sulfate   by
 gavage  to mice for  76-98  weeks and observed a  dose-related Increase  In  the
 Incidence  of liver  carcinomas  (see  Table 6-7).   An  adequate exposure  and
 observation  period was  used  In this study, several dose  levels  of hydrazlne
 sulfate  were administered, a  dose-related Increase  In tumor Incidence  was
 demonstrated and both male and  female  mice were tested.   The only weaknesses
 of  the  study were   that  a  single  species   was   examined  and  statistical
 analysis was not reported.
    Bosan  et al. (1987)  reported  a dose-related Increase  In  hepatocarclnomas
 after  oral exposure  of  Syrian Golden  hamsters to  hydrazlne  sulfate  for  2
 years (see  Table 6-8).   An Increase  In  DNA methylatlon 1n the liver was also
0329d
8-1
01/22/90

-------
 observed.   This was  a  well  conducted chronic  study;  however,  statistical
 analysis was not reported, and only one species was examined.
    Several  other  studies  of oral  exposure  to  hydrazlne  sulfate  In  mice
 demonstrated an  Increase  In  tumor  Incidence,  primarily  lung  or  liver  adenoma
 or  carcinoma.   Although these studies  Indicate  that,  at least  In mice,  the
 lung  Is  equally  sensitive as the liver to  the carclnogenlclty  of hydrazlne,
 they  are of  limited  value for quantitative risk  assessment  because  only one
 dose  level  was  tested and  statistical  analysis  of  the   results  was  not
 reported (Toth  1969,  1972; Roe  et  al.. 1967; Seven and B1anc1f1or1,  1966}
 (see Tables 6-2 to 6-6).
 8.1.3.   Other  Routes.   No  Indication of  carclnogenlclty   was   found  after
 administration of  hydrazlne  by subcutaneous Injection  In rats  once/week  for
 2.5 years  (Stelnhoff  and Nohr,  1988).  Negative  results were  also  reported
 for  rats  given  hydrazlne  by  Intratracheal  Instillation  for  2.5  years
 (Stelnhoff and Nohr,  1988).
8.1.4.   Height  of  Evidence.  Hydrazlne  caused  a  dose-related  Increase  1n
 the   incidence   of   tumor  formation   1n   mice  (lung  adenoma)  and   rats
 (alveolalgenlc carcinoma,  lymphosarcoma of  spleen)  after  Inhalation  exposure
 (NacEwen et  al., 1981).   Oral  exposure to  hydrazlne  caused a  dose-related
 Increase In the  Incidence  of  hepatic  carcinomas  In mice (B1anc1f1or1,  1970d;
 Bosan et al., 1987).  Other  studies also documented Increased lung and liver
 tumor Incidence after oral exposure In  mice (Blandflorl, 1970c; Toth,  1969,
 1972; Roe  et  al.,  1967; Seven and B1anc1f1or1.  1968).   Bosan  et al.  (1987)
observed an  Increased  Incidence of liver  tumors  1n hamsters  treated  orally
with hydrazlne.
    Toth  (1969)  reported  an  Increased Incidence  of  pulmonary adenoma  or
adenocarclnoma In mice  exposed orally to hydrazlne, but  observed a  decrease
 In  the   Incidence  of  mammary gland  carcinomas   In  hydrazlne-treated  female
0329d                               8-2                              07/26/90

-------
 mice.   Toth  (1972)  and BlandfloM  (1970c)  reported  that oral  exposure  to
 hydrazlne  did not  significantly Increase tumor formation In hamsters.
     Hydrazlne 1s genotoxlc 1n prokaryotes,  lower  eukaryotes,  Insects  and  1n
 animal  and human  cells  jhn vitro,  although no effect was  observed  1n  the  In
 vivo mlcronucleus  test  or  the dominant lethal assay In mice (see Table 6-9).
     Data   regarding  the   cardnogenlcUy   of   hydrazlne  1n   humans   were
 Inadequate.    On  the  basis   of   these  data   and   the   U.S.   EPA  (1986c)
 classification   scheme,  hydrazlne  has  been classified   In  EPA  we1ght-of-
 evldence Group B2:  probable human carcinogen (U.S. EPA,  1988,  1989).
 8.1.5.   Quantitative Risk Estimates.
     8.1.5.1.   INHALATION  — The    Inhalation   q^   for    hydrazlne,    17.1
 (mg/kg/day T1. was calculated  from data  reported  1n  MacEwen et  al.  (1981),
 which  documented a  dose-related  Increase 1n the  Incidence of  nasal  cavity
 adenoma or adenocardnoma  1n male  F344 rats.  The corresponding unit risk  Is
 4.9xlQ~3    Ug/mT1.     The    Inhalation    q^   and    unit   risk   for
 hydrazlne  has been reviewed and  verified  by the U.S. EPA  (1989).   The  dose
 associated with  a  risk level of   IxltT5  1s  5.9xlO"7 mg/kg/day.   Multiply-
 ing  this value by the reference human body weight  (70 kg)  and  then dividing
 It  by  the  reference human  Inhalation rate (20 m'/day) yields  a correspond-
 ing  air   concentration  of  2xlO~*  mg/m3.   Air  concentrations  associated
 with  risk  levels   of   lx!0~«  and  lxlO~7   are  2xlO"7   mg/m"  and  2x10~«
 mg/ma, respectively.
    8.1.5.2.   ORAL — The  oral   q^  for  hydrazlne,   3.0   (mg/kg/day)"1,
 was  calculated  from data  reported  by Blanclfforl  (1970a) that  documented a
 dose-related  Increase  1n  the  Incidence  of hepatoma  formation  1n  male  mice
 exposed  to  hydrazlne  sulfate.   The  corresponding  unit  risk  1s  8.5x10~s
0329d
8-3
08/02/90

-------
        4.    The  q-j*   based  on   the   data   for   hydrazlne  sulfate   was
adopted  for hydrazlne  without  adjustment  for  differences  In the  molecular
weights  of the  two compounds.   The  oral  q  *  and  unit  risk for  hydrazlne
have been  reviewed  and  verified  by  the  U.S. EPA (1989).   The dose associated
with  a  risk  level  of  IxltT'   Is  3.3xlO~«  mg/kg/day.   Multiplying  this
value by the reference  human body weight  (70  kg)  and then dividing It by the
reference  human water  consumption  rate   (2  i/day)  yields  a  corresponding
water  concentration  of  l.ZxlCT4  mg/l.    Water   concentrations   associated
with   risk  levels  of   lxlO'«   and   lx!0~7   are  1.2xlO~5  and   1.2x10"*
mg/l, respectively.
8.2.   SYSTEMIC TOXICITY
8.2.1.   Inhalation Exposure.
    8.2.1.1.   LESS     THAN    LIFETIME    (SUBCHRONIC)  — Hydrazlne-lnduced
systemic  tox1c1ty   after  Inhalation exposure  1s   observed  primarily  In  the
liver,  lungs  and  blood.   Dogs  exposed  to 6.6  mg/m»  Intermittently  (Rec.
#3,  Appendix  C.2.1.)   or 1.3   mg/m9   continuously  for  6  months  suffered
decreased  red  blood cell  counts, hemoglobin concentration  and  hematocrlts.
and  Increased   erythrocyte  fragility   (Haun  and   Klnkead,   1973}.   Under  a
similar  exposure  protocol,  death and  fatty  liver  changes  In  mice  at  0.26
mg/m3  (Rec. #1,  Appendix   C.2.1.)  and  moderate  fat accumulation  1n  the
liver  of  rhesus  monkeys  at 1.3 mg/m»  Intermittently   (Rec.  #5,  Appendix
C.2.1.) were observed.  Similarly,  Comstock et al.  (1954) found  fatty liver
changes and death  1n  beagle  dogs exposed  Intermittently  to  18  mg hydrazlne/
                                               3
m3  for  <6 nonths  (Rec. #11. Appendix  C.2.1.).  Comstock and  Oberst (1952)
reported  death,  emphysema and   interstitial  pneumonHls  In  rats  (Rec.  #7,
Appendix C.2.1.),  and  emphysema   and atelectasls  1n dogs  (Rec. #6,  Appendix
C.2.1.)  exposed  to 6 mg  hydrazlne/m1  for  31 weeks.  Chronic  Inflammation,
0329d
8-4
03/28/90

-------
 atelectasls  and lymphold hyperplasla were observed In guinea pigs exposed to
 3-6  mg/m3  for  2  weeks  followed  by  8  weeks  at  4-8  mg/m»  (Weatherby and
 Yard,  1955)  (Rec.  #12,  Appendix C.2.I.).   In the  same  study, pathological
 changes  noted  1n  mongrel dogs  exposed  to  3-6 mg/m3  Included central-zone
 fatty  degeneration  and  necrosis   of   the  liver  and  accumulation   of  bile
 pigment  (Rec.   #13,  Appendix  C.2.I.).   Capillary  damage  In the  kidney and
 lung atelectasls were also observed  (Weatherby and  Yard, 1955).
    The  subchronlc Inhalation  data,  however,  cannot be used  for derivation
 of  an  RfD.  Haun  and  Klnkead (1973)  reported  significant  mortality 1n mice
 exposed  continuously  at 0.2  ppm  (HEC  =  0.26 mg/m*),  which  represents  a
 PEL.   Calculation  of HECs for all  NOAEL and  LOAEL  values  from the  exposure
 concentrations  used  In  other  subchronlc  Inhalation  studies  (Comstock and
 Oberst,  1952;   Heatherby and  Yard,  1955)  were not  lower   than  0.26 mg/m*,
 the HEC for  the PEL In mice.
    8.2.1.2.    CHRONIC — Chronic  Inhalation  data  regarding   hydrazlne are
 also not appropriate  for derivation of a chronic Inhalation RfD.  NacEwen et
 al.  (1981)  observed  respiratory  tract  Inflammation  and  nasal/lung hyper-
 plasla  In  rats  exposed  to  0.05  ppm  (0.06 mg/m*)  hydrazlne 6  hours/day,  5
 days/week  for  1 year  (Rec.  #15, Appendix  C.2.I.).  The HEC at  which  these
 effects  appeared  (0.02  mg/m*)  Is   a   LOAEL  and  Is an  order of  magnitude
 lower  than  the  HEC (0.26 mg/m*)  associated  with significant mortality  In
 mice (Haun and Klnkead,  1973) In a  subchronlc  Inhalation  study.   Therefore,
 U Is not appropriate to derive a chronic Inhalation RfD from this LOAEL.
    Hamsters  exposed to 0.25  ppm   (0.32  mg/m*)  hydrazlne,  6 hours/day,  5
 days/week  (HEC  >   0.057 mg/m*)  for  1  year  had  widespread   toxic  effects
 (amyloldosls  1n the livers,  spleens,  kidneys, thyroids and adrenals,  liver
0329d
8-5
01/22/90

-------
 hemoslderosls,   kidney   mineralization,   senile   atrophy   and  hypospermato-
 genesls)  at  the 2-year  sacrifice  (MacEwen  et al. 1981)  (Rec.  #14,  Appendix
 C.2.I.).  The NEC for  these  effects 1n  hamsters  Is  higher than the  HEC  for
 respiratory  hyperplasla  In  rats.   No  other chronic  Inhalation  studies  were
 located that would be suitable for derivation of an RfD.
8.2.2.   Oral Exposure.
    8.2.2.1.   LESS  THAN LIFETIME  (SUBCHRONIC) - Data regarding  subchronlc
oral  exposure  to hydrazlne  are  Inadequate for  derivation  of  a  subchronlc
oral  RfD.   Blandflorl  (1970a) reported only serious  liver  effects  (cirrho-
 sis,  atrophy and necrosis) after  oral exposure  to hydrazlne  1n hamsters that
received  2.8 mg hydrazlne 5  days/week  for  20 weeks,  or  3.0 mg hydrazlne  4
days/week  for  IS weeks  (Recs. #2 and 3, Appendix C.2.2.).   No other  doses
were  tested; therefore,  these data are not suitable  for  use as LOAEL values
for RfD  determinations.   Sever 1  and  Blandflorl  (1968)  treated mice orally
with  37.7  mg hydrazlne/kg/day but reported only  Increased  tumor  Incidences
and decreased  llfespan.   Weatherby and  Yard  (1955)  administered  hydrazlne
orally at  various  doses;  however,  3/10 rats  died  at  100  mg/i  (Rec.  #1,
Appendix C.2.2.), the lowest concentration tested.
    8.2.2.2.   CHRONIC — Pertinent data  regarding nonneoplastU effects  of
chronic oral exposure  of humans  or animals to  hydrazlne  were not  located 1n
the  available   literature  cited   In  Appendix  A.   Therefore,   no  data  are
available for derivation of a chronic oral RfD.
0329d
8-6
01/22/90

-------
                           9.   REPORTABLE  QUANTITIES
9.1.   BASED ON SYSTEMIC TOXICITY
    The  toxlclty  of hydrazlne  was  discussed  In  Chapter  6.  A chronic  non-
cancer toxlclty RQ  has  been derived  for  hydrazlne {U.S.  EPA,  1985),  based  on
mortality  In  mice  exposed Intermittently  to  1.3 mg/m*  for  6 months  (Haun
and Klnkead,  1973), and 1s summarized  1n Table 9-1.  More recent data  were
not  located;  hence, there  has  been no  reconsideration  of this  derivation.
The RQ of  10  derived by U.S.  EPA (1985)  Is adopted  for the purposes of  this
document.
9.2.   BASED ON CARCINOGENICITY
    Data regarding  the  cardnogenldty of  hydrazlne  are discussed  1n Chapter
6 and presented 1n  Tables  6-1  through  6-8.   Several  studies have  reported  an
Increase 1n tumor Incidence after Inhalation and  oral  exposure  to  hydrazlne.
NacEwen  et  al. (1981)  observed significantly  Increased  Incidences  of  lung
adenomas  In  mice,  nasal  cavity adenomas  and  adenocarclnomas  In  rats, and
nasal  cavity  polyps  1n hamsters,  after   Inhalation  exposure to  hydrazlne.
B1anc1f1or1 (1970a)  observed  a  dose-related  Increase In hepatic  carcinomas
after oral  exposure to hydrazlne.   Other studies also documented Increased
lung and  liver tumor  Incidences  after oral exposure  1n  mice  (Blandf 1or1,
1970c; Toth.  1969,  1972;  Roe  et al., 1967;  Seven  and  BlandfloM,  1968).
An  increase  in liver  tumor incidence was also  reported 1n  hamsters after
oral exposure to hydrazlne (Bosan et al.,  1987).
    The  genotoxldty  of   hydrazlne  has   been  demonstrated  1n prokaryotes,
lower eukaryotes,  Insects  and  1n human  and animal  cells jn vitro (Table 6-9).
0330d                               9-1                               08/01/90

-------
                                   TABLE  9-1
                                   Hydrazlne
                                  (302-01-2)
           Minimum Effective  Dose  (MED) and Reportable Quantity  (RQ)
Route:
Species/sex:
Oose*:
Duration:
Effect:
RVd:
RVe:
CS:
RQ:
Reference:
Inhalation
mouse/female
1.6 rag/day
6 months
mortality
5.2
10
52
10
Haun and Klnkead, 1973
'Equivalent human dose
0330d
            9-2
01/22/90

-------
     On  the basis of  the  available data, hydrazlne has  been  assigned to EPA
 we1ght-of-evidence  group  82 as a  probable  human  carcinogen  (U.S.  EPA, 1988,
 1989).
     A  human potency  factor  has been  derived  (U.S.  EPA, 1988)  based on the
 incidence  of  nasal  tumors  In rats  (MacEwen et a!., 1981) and Is presented 1n
 Table  9-2.  On  the basis of  this potency factor, hydrazlne  1s assigned to
 the  "high"  potency  group,  which,   for   EPA  we1ght-of-evidence  Group  82
 chemicals,  results  In a cancer-based RQ of  1.
0330d                               9-3                              01/22/90

-------
                                   TABLE  9-2

                Derivation of Potency Factor (F) for Hydrazlne
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle or physical state:
Body weight3:
Duration of treatment:
Duration of study:
Llfespan of animal:
Target organ:
Tumor type:
Experimental doses/exposures:
Transformed dosesb:
(mg/kg/day)
Tumor Incidence:
Animal Potency (mg/kg/day)"1:
Human Potency0:
{ mg/kg/day T1
MacEwen et al. ,
Inhalation
rat
F344
M
air
0.35 kg
365 days
910 days
910 days
nasal cavity
1981



M
air
365 days
910 days
910 days





N
air
NA
910 days
910 days

adenoma/adenocarclnoma
5.0 ppm
0.30
72/99
19.33

1.0 ppm
0.06
11/98


0.0 ppm
0.0
0/149


Estimated
bTo derive  the transformed  doses  from the  experimental  dose data,  convert
 experimental dose  1n  (ppm) to  (mg/m>):  0.041  x mol wt  hydrazlne  x  concen-
 tration  (ppm); calculate  preliminary transformed dose (mg/kg/day) based  on
 breathing  rate  and animal  weight:  concentration  (mg/m*)  x breathing  rate
 for  rats  (0.22  m»/day)/an1mal  weight   (0.35  kg);  determine  final  trans-
 formed dose by adjusting for  duration of study,  and discontinuous  exposure:
 transformed  dose  (mg/kg/day)  x  duration of  treatment  (days)/durat1on  of
 study  (days) x 5 (treatment days/week)/? (days/week) x  6  (treatment hours/
 day)/24 (hours/day).                          :

cHuman potency « animal potency x (70 kg/0.35 kg)1/3

NA - Not available
0330d
9-4
03/28/90

-------
                                10.  REFERENCES

 ACGIH  (American  Conference of  Governmental   Industrial  Hyg1en1sts).   1989.
 Threshold  Limit  Values  and  Biological  Exposure  Indices  for  1980-1990.
 Cincinnati, OH.   p. 26, 44.

 Agrelo,  C  and H.  Amos.   1981.   ONA  repair  1n  human  flbroblasts.   Prog.
 Mutat. Res.  1: 528-532.

 Amoore,  J.E. and  E.  Kautala.   1983.   Odor as  an aid to chemical safety: Odor
 thresholds compared with  threshold limit  values and volatHes for  214 Indus-
 trial chemicals 1n air and water dilution.  J. Appl. Toxlcol.  3: 272-290.

 Anderson, D. and  J.A.  Styles.   1978.   An  evaluation of four short-term tests
 for  detecting  organic  chemical  carcinogens.   Appendix  2.  The  bacterial
 mutation test.  Br. J. Cancer.  37: 924-930.

 Applegate, V.C.,  J.H.  Howe11,  A.E. Hall,  Jr.  and  M.A.  Smith.  1957.   Toxlc-
 Hy  of  4346  chemicals to  larval  lampreys and fishes.   Special  Scientific
 Reports Fisheries No. 207.  F1sh U11dl. Sen.,  USDI, Washington. DC.  157 p.

 Atkinson, R. and  U.P.L.  Carter.   1984.  Kinetics and mechanisms of gas-phase
 reaction  of  ozone  with  organic   compounds   under  atmospheric  conditions.
 Chem. Rev.  84: 437-470.

 Bach,  M.K.   1957.   Hydrazlne  and biological  nitrogen  fixation.   Blochem.
 Blophys. Acta.  26: 104-113.


0331d                               10-1                             08/09/90

-------
 Balganesh,  H.  and  J.K.  Set low.   1984.   Prophage Induction  In  HaemophHus
 Influenzae and Us relationship to mutation by chemical and physical  agents.
 Mutat. Res.  125: 15-22.

 Barrows, L.R.  and  R.C.  Shank.  1981.  Aberrant methylaUon  of  liver  ONA In
 rats during hepatoxlclty.   Toxlcol.  Appl.  Pharmacol.  60(2): 334-345.

 Bhlde, S.V., R.A. D'Souza,  M.M.  Sawal  and K.J.  Ranadlve.   1976.   Lung tumor
 Incidence  In mice  treated  with hydrazlne sulfate.   Int.  J.  Cancer.   18(4):
 530-535.

 Blanclflorl, C.   1970a.   Hepatomas 1n CBA/Cb/Se  mice  and liver  lesions  1n
 golden hamsters  Induced  by hydrazlne  sulfate.   J.  Natl.   Cancer  Inst.   44:
943-953.

Blanclflorl, C.  1970b.  Tumor 1  polmonaM ed epatld  da  1draz1na  solfato a
dose rldotte  1n  top! BAL8/c/Cb/Se.  Lav.  Anat.  Univ.  Perugia.   30:  89-99.
 (Ital.)

BlandMoM, C.   1970c.   Ovarian  Influence  on pulmonary  cardnogenesls  by
hydrazlne sulfate 1n  BALB/c/Cb/Se  mice.   J. Natl. Cancer Inst.  45: 965-970.

Blanclflorl,  C.   1970d.   Cancerogenesl   da   Idrazlna  solfato 1n  traplantl
 1sogen1c1  tracheo-broncopolmonarl  In  topi  BAU/c/Cb/Se.   Lav.  Anat.  Univ.
Perugia.  30: 137-146.   (Ital.)
0331 d
10-2
08/09/90

-------
 BlanclMorl,  C.   1971.  Influenza  degll  ormon!  ovarld  nella cancerogenesl
 polmonare da  Idrazlna  solfato  In  tope C3Hb/Cb/Se.  Lav. Anal. Univ. Perugia.
 31: 5-17.  (Hal.)

 BlandfloH,  C. and R.  R1bacch1.  1962a.  The Induction of pulmonary tumours
 In  BABL/c  mice by oral  administration  of  1son1az1d.   In:  The Morphological
 Precursors of Cancer,  I.  Severl,  Ed.   Division  of Cancer Research, Perugia.
 (CHed 1n IARC, 1973)

 81anc1f1oM,  C. and R.  Rlbacchl.   1962b.   Pulmonary  tumours  1n  mice Induced
 by oral Isonlazld and  Us metabolites.   Nature (London).  194: 488-489.

 B1andf1oM,  C. and L. Severl.   1966.  The  relation  of  Isonlazld  (INH)  and
 allied  compounds   to   cardnogenesls  In  some  species  of  small  laboratory
 animals: A review.  Br. 3.  Cancer.  20:  528-538.

 BlandfloH.  C..  E.  Bucc1arel11,  F.E.  Sant1111 and  R. Rlbacchl.   1963a.
 Cardnogenesl  polmonare  da  Idrazlde dell1 acldo  1son1cot1n1co  (INI) e  suol
 metabolltl  In topi  CBA/Cb/Se  substraln.   Lav.   Anat.  Univ. Perugia.   23:
 209-220.  (Ital.)

 Blandflorl.  C.,  R.  Rlbacchl, E.  Bucc1arell1,   P.P.  D1Leo  and  U.  Mllla.
 1963b.  Cancerogenesl   polmonare da  Idrazlna  solfato  In topi  femmlne BALB/c.
 Lav. Anat. Univ.  Perugia.  23:  115-127.  (Hal.)
0331 d
10-3
08/09/90

-------
 BlandMoM,  C..  E.  Bucc1are111,  0.8.  Clayson  and  F.E.  SantUU.   1964.
 Induction  of  hepatomas  1n CBA/Cb/Ce mice by hydrazlne sulphate and the  lack
 of  effect  of croton  oil  on tumour  Induction  In  BALB/c/Cb/Se mice.   Br.  J.
 Cancer.  18: 543-550.

 Bosan,  W.S.,  R.C.  Shank,  J.O.  MacEwen, C.L.  Gaworskl   and  P.M. Newberne.
 1987.   Nethylatlon  of DMA  guanlne  during the  course  of Induction of liver
 cancer  1n  hamsters  by   hydrazlne   or  d1methy1n1trosam1ne.   Cardnogenesls
 (London).  8(3): 439-444.

 Carter, V.L., Jr.,  K.C.  Back and J.C. MacEwen.  1981.   The oncogenlc hazard
 from  chronic  Inhalation  of hydrazlne.  In:  Proc. A6ARD  Conf.   A6ARD-CP-309.
 p. B5/1 to B5/9.

 Chemllne.  1989.   Chemical  Information Service (CIS).  Online:  July 8. 1989.
National Library of Medicine.

 Cornstock,  C.C.   and  P.M.  Oberst.   1952.   Chronic  Inhalation  toxldty  of
hydrazlne vapors to dogs  and rats.  Fed.  Proc.   11:  333.

 Cornstock, C.C., L.H.  Lawson, E.A. Greene and P.M. Oberst.   1954.   Inhalation
 toxlclty of hydrazlne vapor.  Arch.  Ind.  Hyg.  Occup.  Med.  10: 476-490.

 Cortl,  U.A.  1950.   Fish  and nitrogen compounds.  The "matrix* of fish.  XI.
 Verh. Intl. Ver. Llmnol.   11: 84-87.  (Fre.)
0331d                               10-4                             08/09/90

-------
 Crockett,  P.M.,  B.  Klllan,  K.S.  Crump  and  R.B.  Howe.   1985.   Descriptive
 Methods  for Using Data  from Dissimilar  Experiments  to  Locate a  No-Adverse-
 Toxic-Effects  Region 1n  the Dose-Duration Plane.  Prepared by K.S. Crump and
 Company,  Inc.  under  Contract No. 6807-007 for the  Environmental Criteria and
 Assessment  Office, Cincinnati,  OH.

 Dambrauskas,  T. and  H.H.  Cornish.  1964.  The  distribution,  metabolism and
 excretion  of  hydrazlne  In  rat and  mouse.   Toxlcol.  Appl.  Pharmacol.   6:
 653-663.

 Dean,  B.J.   1981.   Activity  of  27  coded compounds  In the  RU  chromosome
 assay.  Prog.  Mutat. Res.   1: 570-579.

 Dlamantls,  A.A.  and  E.R.  Roberts.   1960.  Studies  In the biological fixation
 of  nitrogen.   X. Disappearance of hydrazlne  from cultures  of A.  vlnelandll.
 Blochem. Blophys. Acta.  42:  76-91.

 Dost, F.N.,  D.J.  Broderlck,  B.M.  Krlvak and D.J. Reed.  1981.  Metabolism of
 hydrazlne.  Report.  ISS AFAHRL-TR-81-26.  NTIS  AD-A101849.

 Durkln,  P.  and  U.  Meylan.   1989.   Users' Guide  for D2PLOT:  A  Program for
 Dose/Duration  Graphs,  Version 2.00.   Prepared  by Chemical  Hazard Assessment
 Division,  Syracuse  Research  Corporation  under  Contract No.  68-C8-0004 for
 the Environmental Criteria and Assessment  Office, Cincinnati, OH.

 Elsenrelch,  S.J.,  B.B.  Looney  and  J.D. Thornton,   1981.   Airborne organic
 contaminants  1n  the Great  Lakes  ecosystem.   Environ.  Scl.  Technol.   15:
 30-38.

0331d                               10-5                             08/09/90

-------
 Ellis,  S.R.M.,  6.V.  Jeffreys and P. Hill.  1960.  Oxidation  of  hydrazlne  1n
 aqueous solution.  J. Appl. Ghent.  10:  347-352.

 Epstein,  S.S.,  E.  Arnold, 0.  Andrea.  U.  Bass and Y.  Bishop.   1972.   Detec-
 tion  of  chemical  mutagens   by  the  dominant  lethal   assay  1n  the  mouse.
Toxlcol. Appl. Pharmacol.  28: 288-324.

Fisher, J.W.,  C.B.  Harrah,  L.K. Weaver  and  U.I. W1ngo.   1976.  Acute  and
behavioral effects of hydrazlne  on  Lepomls  roacrochlrus.   Aerospace Ned.  Res.
Lab., Wright-Patterson AFB, OH.  NTIS AD-A057072.

Fisher, J.H., C.B. Harrah and W.O.  Berry.  1980a.   Hydrazlne acute  toxldty
to bluegllls and sublethal  effects  on  dorsal  light  response  and aggression.
Trans. Am. F1sh. Soc.  109(3): 304-309.

Fisher, J.M.,  D.S.  Myers  and M.L.  Myers.   1980b.   The effects  of  selected
hydrazlnes upon fish  and Invertebrates.   Tech. Rep.  Aerosp.  Ned. Res.  Lab.,
Govt. Rep. Announce.  Index.

Frost,  0.  and N.  Hjorth.   1959.  Contact  dermatitis  from hydrazlne  hydro-
chloride  In  soldering flux — Cross sensHlzatlon  to Apresollne and  1son1-
azld.   Acta.  Derm.  Venereol.   38:  82-86.   (In  German  with English  trans-
lation)
                                              4
Gormley.  W.T.  and  R.E.  Ford.   1973.   Oeoxygenatlon of  environmental  waters
by hydrazlne-type fuels.  Proc. Annu.  Conf. Environ.  Toxlcol.   p. 387-400.
0331 d
10-6
08/09/90

-------
 Green.  H.H.   1981.   A differential  killing  test using  an Improved repair-
 deficient  strain of  Escherlchla  coll.   prog.  Mutat.  Res.   1: 183-194.

 Greenhouse,  G.A.  1976.   The evaluation of the toxic effects of chemicals  In
 fresh  water  by  using  frog  embryos  and  larvae.    Environ.  Pollut.   11(4):
 303-315.

 Greenhouse,  G.A.  1977.  Toxldty  of  N-phenyl-alpha-napthlyamlne  and hydra-
 zlne  to Xenopus  laevls embryos  and  larvae.   Bull.  Environ. Contarn. Toxlcol.
 18(4):  503-511.

 Hansch,  L.  and  A.J.  Leo.    1985.   MedChem  Project.   Issue No.  26,  Pomona
 College, Claremont,  CA.

 Haratl, Y.  and E. Nlakan.   1986.  Hydrazlne toxlclty, pyrldoxlne therapy and
 peripheral neuropathy.  Ann.  Intern. Ned.  104: 728-729.

 Harrah, C.B.   1977.   Biological  effects of aqueous  hydrazlne solutions.   In:
 Proc.  Conf.  Environ.  Chem.  Hydrazlne  Fules,  Tyndall  AFB,  FL,   Air  Force
 Technical Report, CEEDO-TR.

 Harris, G.H..  R. Atkinson  and J.N. Pitts,  Jr.   1979.  Kinetics of the reac-
 tions of  the OH  radical with hydrazlne and  methyhydrazlne.   J.  Phys.  Chem.
 83: 2557-2559.

 Haun, C.C.  and  E.R. Klnkead.   1973.   Chronic Inhalation  toxlclty  of  hydra-
 zlne.   In:  Proc. Ann. Conf.  Environ.  Toxlcol.   p.   351-363.   (Cited  In  U.S.
 EPA, 19845)

0331d                               10-7                             08/09/90

-------
 Hayon,  E.  and  M.  S1m1c.   1972.   Intermediates  produced  from the one-electron
 oxidation  of hydrazlne.   Evidence  for  the  formation and decay  of  tetrazone
 and trlazene.  J. Am. Chem. Soc.  94: 42-47.

 Helnemann,  B.   1971.   Prophage Induction In lysogenlc  Escherlchla  coll  with
 simple hydroxylamlne and hydrazlne compounds.  Appl. Mlcroblol.  21: 726-731.

 Hemmlnkl,  K.  and  H. Va1n1o.   1984.   Human  exposure  to  potentially carcino-
 genic  compounds.   IARC  Sd.  Publ.  59  (Monlt.  Hum.  Exposure  Carclnog.
 Mutagen. Agents): 37-45.

 Henderson,  V.  J.H.  Fisher and  R.  D'Allessandrls.  1981.   Toxic  and terato-
 genlc effects  of  hydrazlne on  fathead minnow  (Plmephales  promelas) embryos.
 Bull.  Environ. Contam. Toxlcol.  26(6): 807-812.

 Herbold,  B. and  H.  Buselmaler.    1976.   Induction  of point mutations  by
different  chemical  mechanisms  1n  the  liver  mlcrosomal assay.   Mutat.  Res.
 40(2): 73-83.

 HSOB  (Hazardous  Substance  Data  Base).   1989.   On-line  July  12,  1989.
National Library of Medicine.

Hunt,  T.P.,  J.W.  Fisher, J.M.  Livingston and  M.E.  Putnam.   1981.   Tempera-
 ture  effects on  hydrazlne  toxlclty  to bluegllls.   Bull.  Environ.  Contam.
Toxlcol.  27(5): 588-595.
0331 d
10-8
08/09/90

-------
 IARC  (International  Agency for Research on  Cancer).   1973.   IARC Monographs
 on  the  Evaluation  of  the  Carcinogenic  Risk  of  Chemicals  to  Man.   Some
 Aquatic  Amines, Hydrazlne  and Related  Substances,  N-NHroso  Compounds  and
 Miscellaneous  Alkylatlng Agents:  Hydrazlne.  IARC, WHO,  Lyon,  France.   Vol.
 4, p. 127-133.

 Jacobson,  K.H., J.H.  Clem,  H.J.  Wheelwright.  U.E. Rlnehart  and N.  Hayes.
 1955.  The acute toxkUy  of  the  vapors  of some methylated hydrazlne deriva-
 tives.  Arch.  Ind. Health.  12: 609-616.

 James,  D.E.,  S.L.  Manley,  M.C.  Carter  and W.J.  North.   1987.  Effects  of
 PCBs and  hydrazlne  on  life  processes  1n  microscopic  stages of selected brown
 seaweeds.  Hydroblologla.  p. 151-152, 411-415.

 Kane, D.A. and K.J.  Williamson.   1983.   Bacterial  tox1c1ty and metabolism of
 hydrazlne fuels.  Arch.  Environ. Contam.  Toxlcol.  12:  447-453.

 Kaneo, Y.,  S.  Iguchl, H.  Kubo,  N. Iwag1r1 and K.  Natsuyama.   1984.   Tissue
 distribution of hydrazlne and Us metabolites  1n  rats.   J.  Pharmacob1o-Dyn.
 7(8): 556-562.

 Keller, W.C.,  C.T. Olson, K.C.  Back and  C.L.  Gaworskl.   1982.   Evaluation of
 the  embryotoxIcHy  of  hydrazlne  In rats.    A1r  Force  Aerospace  Medical
 Research Lab, Wright-Patter son AFB. OH.   p. 16'.   (CA 98:12702$)
0331d                               10-9                             08/09/90

-------
 Keller,  U.C.,  J.P.F.  Murphy,  R.H.  Bruner,  M.E.  Andersen  and  C.T.  Olson.
 1984.    Tox1cok1net1cs   of  Hydrazlne  Administered   Percutaneously   to  the
 Rabbit.   Air  Force  Aerospace Medical  Research  Lab., Wright-Patterson  AFB,
 OH.  ADA143122.
Kelly,  M.G.,  R.W.  O'Gara,  S.T.  Yancey,  K.  Gadekar,  C.  Botkin  and  V.T.
Ollverlo.    1969.    Comparative  cardnogenldty   of   N-1sopropyl-alpha-{2-
methy1-hydraz1no)-p-to1uam1de    -HC1    (procarbazlne    hydrochlorlde),    its
degradation  products,  other  hydrazlnes and  1son1cot1n1c  acid hydrazlne.   3.
Natl. Cancer Inst.  42: 337-344.

Lee,  S.H.  and  H.  Aleyasslne.   1970.   Hydrazlne  toxlclty 1n pregnant  rats.
Arch. Environ.  Health.  21: 615-619.

Lemontt, J.F.   1978.   Loss of hydraz1ne-1nduced mutability  In wild  type and
excision  repair defective yeast  during  post-treatment  Inhibition  of  cell
divisions.  Mutat. Res.  50: 57-66.

Lemontt, F.J.  and S.V.  Lair.   1982.   Plate  assay for chemical- and  radia-
tion-Induced mutagenesls  of canl  In yeast as  a  function of post-treatment
DNA replication: The effect of rad6-l.  Mutat. Res.  93: 339-352.

I1u.  D.H.W.  and R.E.  Nakatanl.   1964.   Toxlclty  of  Industrial  chemical  to
fish.   In:  Biology  Research  Annual  Report  for   1963,  HW-80500.   Hanford
Atomic Products Operation, RUhland, UA.  p. 209-211.
0331d
10-10
08/09/90

-------
 Llewellyn,  B.M.,  H.C.  Keller  and  C.T.  Olson.  1986.  Urinary Metabolites of
 Hydrazlne   1n  Hale  Fischer  344 Rats  Following  Inhalation  or  Intravenous
 Exposure.   Harry G.  Armstrong Aerospace   Medical  Research  Lab,  Wright-
 Patterson AFB, OH.   Report  No. AAMRL-TR-86-025.

 Lyng,  R.D., W.C.  Keller  and K.C. Back.   1980.  Effects of hydrazlne on preg-
 nant  ICR mice.   Air Force Aerospace Medical  Research  Lab,  Wright-Patterson
 AFB, OH.  p. 12.  (CA 93:162242c)

 MacEwen,  J.D.,  E.R. Klnkead,  E.H.  Vernot,  C.C.  Haun and A.I.  Hall.   1981.
 Chronic  Inhalation   toxldty  of  hydrazlne:  Oncogenlc  effects.   ISS  AFAMRl-
 TR-81-56.   NTIS AD-A101847.

 MacNaughton,  M.G.   1979.   Environmental  fate of  hydrazlne.   In:  Proc. Prpt.
 Annu.  Sd. Meet.  - Aerosp. Med.  Assoc.  p. 31-32.

 MacNaughton.  M.G.,  J.  Zlrrolll,   T.B.   Stauffer,   and   O.A.  Stone.   1979.
 Environmental  chemistry of  hydrogen fuels.   In:  Proc.  9th  Conf.  Environ.
 Toxlcol.,  March,  Aerosp.   Med.  Res.  Lab.,  Aerosp.  Med.   01v..  Air  Force
 Systems  Command,  Wright-Patterson   A1r   Force  Base,   OH.    AMRL-Tr-79-68.
 p. 121-128.

 MacNaughton, M.G., T.B.  Stauffer and  D.A.  Stone.   1981.   Environmental chem-
 istry  and  management of  hydrazlne.   In:  Aviation,  Space, and Environmental
 Medicine (March),  p. 149-153.
0331d                               10-11                            08/09/90

-------
 MacRae,  W.D.  and H.F.  Stlch.   1979.   Induction of sister  chromatld exchanges
 1n  Chinese hamster  ovary cells  by  thlol  and hydrazlne compounds.   Nutat.
 Res.  68:  351-365.

 Mantel,  N.  and  M.A.   Schnelderman.    1975.    Estimating  "safe"  levels,  a
 hazardous  undertaking.  Cancer Res.  35: 1379-1386.

 Martin,  C.N.  and A.C.  McDermld.   1981.   Testing of 42 coded  compounds  for
 their ability  to Induce unscheduled ONA repair synthesis  In  Hela cells.  In.:
 Evaluation  of  Short-term  Tests for Carcinogens:  Report  of  the International
 Collaborative  Program.  Prog. Mutat.  Res.  1: 533-537.

 McDougall,  K.J.  and  J.F.  Lemontt.  1979.  Effects of  spermlne  on the detec-
 tion  of  Induced  forward  mutation at  the  canl  locus In yeast:  Evidence  for
 selection against canavanlne-reslstant mutants.  Mutat. Res.   63: 21-34.

 McKennls.  H.   Jr., J.H.  Heatherby and  L.B. Ultkln.   1955.   Studies  on  the
 excretion  of   hydrazlne  and  metabolites.    J.  Pharmacol. Exp.  Ther.   114:
 385-390.

 NcKennls, H.,  Jr.. A.S. Yard,  J.H. Weatherby and  J.A.  Hagy.   1959.  Acetyla-
 tlon  of  hydrazlne and  the formation of  1.2-d1acety1hydraz1ne in  vivo.   J.
 Pharmacol. Exp. Ther.  126: 109-116.
Mllla, U.   1965.   Tumor1  polraonaM da 1draz1na solfato  sonmlnlstrata  a topi
neonatl  del  BALB/c/Cb/Se substrain.   Lav.  Anat.  Univ.  Perugia.   25:  73-81.
(Hal.)
0331 d
10-12
08/09/90

-------
 Mill,  T. and H.  Mabey.   1985.   Photochemical  transformations.  In: Environ-
 mental  Exposure from Chemicals,  Vol.  1, W.E. Neely  and  G.E,  Blau, Ed.  CRC
 Press,  Boca  Raton,  FL.   p.  207.

 Nelson,  S.D. and  W.P.   Gordon.   1982.   Hetabollc  activation  of hydrazlnes.
 Adv. Exp. Med.  B1ol.  136B: 971-981.

 NIOSH   (National   Institute   for  Occupational  Safety  and  Health).   1978.
 Criteria  for a Recommended  Standard...Occupational  Exposure  to  Hydrazlne.
 OHEW (NIOSH) Publ.  No. 78-172.

 Noda,  A.,  M. Ishlzawa,  K.  Ohno,  T. Sendo  and  H.  Noda.   1986.  Relationship
 between  oxldatlve  metabolites  of  hydrazlne and  hydrazlne-lnduced rautagen-
 1c1ty.  Toxlcol. Lett. (Amst).  31(2): 131-137.

 Olln  Corporation.   1979.   Study  Reporting  Incidence of  Myocardlal  Infarc-
 tions  In Hydrazlne Workers  with Attachments.  Ol1n Corporation submission to
 U.S. EPA.  FYI-OTS-0279-0021.

 Olln Corporation.   1986.   Final  Report:  Clinical Ep1dem1olog1cal  Study of
 Heart  Attacks  Among Hydrazlne Workers.  Olln  Corporation submission to U.S.
 EPA.  FYI-OTS-0286-0021, Suppl. B.

 OSHA   (Occupational  Safety  and  Health  Administration).   1989.   Code  of
 Federal Regulations 29 CFR 1910.  Federal Register.  54:  12.
0331d                               10-13                            08/09/90

-------
 Ou,  L.  1987.   M1crob1al  degradation  of hydrazlne.  Bull.  Environ.  Contain.
 Toxlcol.   39: 78-85.

 Ou,  L.T.  and   J.J.  Street.   1987.   H1crob1al  enhancement  of  hydrazlne
 degradation In soil and water.  Bull. Environ. Contain. Toxlcol.  39: 541-548.

 Perry,  P.E.  and  E.J.  Thomson.   1981.   Evaluation of  the  sister  chromatld
 exchange method  In mammalian  cells  as  a  screening system  for  carcinogens.
 Prog. Mutat. Res.  1: 560-569.

 Qu1ntero-Ru1z,  A.,  L.L.   Paz-Ner1  and  S.   V1lla-Trev1no.   1981.   Indirect
 alkylatlon of CBA  mouse liver DMA and RNA  by  hydrazlne in  vivo.   A possible
mechanism of action as a carcinogen.   3.  Natl. Cancer  Inst.   67(3): 613-618.

Reid, F.J.   1965.  Hydrazlne poisoning.  Br. Ned. J.  5472:  1246.

Roe. F.J.C., 6.A.  Grant and  D.N.  Mllllcan.   1967.   CarclnogenlcUy of hydra-
 zlne and 1,l-d1methylhydraz1ne for mouse lung.  Nature (London).   216: 37S.

Rogers, A.M.  and  K.C.  Back.  1981.   Comparative  mutagenldty of  hydrazlne
and  3  methylated  derivatives  In  L5178Y mouse  lymphoma  cells.   Mutat.  Res.
89(4): 321-328.
Rowland,  L.  and  B. Severn.   1981.   MutagenlcUy  of  carcinogens  and  non-
carcinogens  In  the Salmonella/mlcrosome test.  In.: Evaluation  of  Short-term
Tests  for  Carcinogens:  Report  of  the International  Collaborative  Program.
Prog. Mutat. Res.  1: 323-332.
0331d
10-14
08/09/90

-------
 Ruth,  J.H.   1986.   Odor thresholds and Irritation levels of several chemical
 substances:  A  review.   Am.  Ind. Hyg. Assoc. J.  47: A-142 to A-151.

 Schlessl,  H.M.   I960.   Hydrazlne  and  Its   derivatives.   1^:  K1rk-0thmer
 Encyclopedia  of Chemical  Technology,   3rd  ed.,  Vol.  12,  M.A.  Grayson,  Ed.
 John Wiley and  Sons, New York.  p. 734-771.

 Schiller, C.M.,  R.  Maiden  and I.E. Kee, Jr.  1979.  Effects of hydrazlne and
 Its  derivatives  on  the   development   of  Intestinal   brush border  enzymes.
 Toxlcol. Appl.  Pharmacol.  49(2):  305-311.

 Seller,  J.P.   1977.    Inhibition  of  testlcular  DMA  synthesis  by  chemical
 mutagens and  carcinogens.   Preliminary results 1n the validation  of  a  novel
 short-term test.  Mutat. Res.  46: 305-310.

 Sever 1,  1.  and  C.  B1anc1Hor1.    1967.   Cancerogenesl   epatlca  ne1  topi
 CBA/Cb/Se/  e   ne1  rattl  Cb/Se   da   Idrazlna  solfato.    Epatologlca.    13:
 199-208.  (Hal.)

 Sever 1,  L.  and  C.  B1anc1f1or1.   1966.  Hepatic carclnogenesls  1n CBA/Cb/Se
 mice and Cb/Se  rats  by 1son1cot1n1c  add  hydrazlde  and hydrazlne  sulfate.
 J. Natl. Cancer  Inst.  41: 331-349.

 Shukla,  P.T.   1972.  Analysis of  mutagen specificity In Orosophlla  melano-
 gaster.  Mutat.  Res.  16: 363-371.
033Id                               10-15                            08/09/90

-------
 Slna,  J.F.,  C.L.  Bean, G.R.  Dysart.  V.I. Taylor  and H.O. Bradley.   1983.
 Evaluation  of the  alkaline  elutlon/rat  hepatocyte assay  as  a predictor  of
 cardnogen1c/mutagen1c  potential.  Mutat. Res.  113(5): 357-391.
Slonlm,  A.R.  1977.   Acute toxlclty  of  selected  hydrazlnes  to the  common
guppy.  Water Res.  11(10): 689-895.

Slonlm,  A.R.  1966.   Acute toxldty  of  some  hydrazlne  compounds  to  sala-
mander larvae, Ambvstoma spp.  Bull. Environ. Contain. Toxlcol.   37:  739-746.

Slonlm,  A.R.,  and  J.B.  Glsclard.   1976.   Hydrazlne degradation 1n  aquatic
systems.  Bull. Environ. Contam. Toxlcol.   16: 301-309.

Smith, E.B.  and  D.A.   Clark.   1972.   Absorption of  hydrazlne  through  canine
skin.  Toxlcol. Appl.  Pharmacol.  21: 186-193.

Sobel, M.,  G.G.  Bond, B.J.  Skowronskl, P.J. Brownson and  R.R.  Cook.   1987.
A soft tissue  sarcoma case control  study In  a  large multl-chemical  manufac-
turing facility.   Chemosphere.  16(8/9): 2095-2099.

Sotanleml,  E.,  J.  Hlrvonen,  H.  Isomakl,  J. Takkunen  and  J.  Kalla.   1971.
Hydrazlne toxldty  1n the  human —  Report of a  fatal case.  Ann. Clln.  Res.
3: 30-33.
Sotomayor,  R.E.,  P.S.   Chauhan   and   U.K.   Ehllng.    1982.    Induction  of
unscheduled DNA  synthesis  1n  the  germ cells of  male mice after  treatment
with hydrazlne or procarbazlne.  Toxicology.  25(2-3): 201-211.
0331 d
10-16
08/09/90

-------
 Southgate,  B.A.   1950.  Polluting effects  of  sewage  and Industrial wastes -
 Toxlclty of substances to  fish.   Ann.  Report  Water Pollut. Res. Bd.  (Cited
 1n  McKee and Wolf,  1963)

 Springer.  D.L.,  B.M.  Krlvak,  O.J. BrodeMck, O.J. Reed and F.N. Dost.  1981.
 Metabolic  fate of hydrazlne.   J.  ToxHol. Environ.  Health.  8(1-2): 21-29.

 SRI   (Stanford   Research   Institute).   1989.   1989  Directory  of  Chemical
 Producers:  United  States   of  America.   SRI  International, Menlo  Park,  CA.
 p.  577,  688.

 Stauffer,  T.B.   1977.   Hydrazlne evaporation.   In:  Proc. Conf.  Env.  Chem.
 Hydrazlne Fuels, Tyndall AFB.  NTIS AD-A054194.  p. 25-38.

 Stelnhoff,  0.  and U.  Mohr.  1988.  The question  of  carcinogenic  effects of
 hydrazlne.  Exp. Pathol.   33(3):  133-143.

 Stone.  D.A,  F.L. Wiseman,  J.E.  Kllduff,  S.L.  Koontz and  D.D.  Davis.   1989.
 The  disappearance  of fuel  hydrazlne  vapors  1n  fluorocarbon-fllin environ-
 mental  chambers.   Experimental observations and  kinetic  modeling.   Environ.
 Sc1. Techno!.  23: 328-333.

 Toth,  B.   1969.   Lung tumor  Induction  and  Inhibition  of  breast adenocarcl-
 nomas  by hydrazlne sulfate  1n mice.  J. Natl. Cancer Inst.  42: 469-475.

 Toth,  B.   1971.   Investigations  on the relationship  between  chemical  struc-
 ture and  carcinogenic activity of substituted hydrazlnes.  Proc.  Am.  Assoc.
 Cancer Res.  12: 55.

0331d                               10-17                            08/09/90

-------
 Toth,  8.   1972a.   Hydrazlne.  methylhydrazlne  and  methylhydrazlne  sulfate
 cardnogenesls  In Swiss  mice.   Failure  of  ammonium hydroxide  to Interfere  In
 the development of tumors.  Int. J. Cancer.  9: 109-118.

 Toth,   B.    1972b.    Tumour 1genes 1s   studies  with   1,2-dlmethylhydrazlne
 dlchloMde,  hydrazlne  sulfate   and   1son1cot1n1c  acid  1n  golden  hamsters.
 Cancer Res.  32:  804-807.

 Tsuchlmoto, T.  and B.E. Matter.   1981.   Activity  of coded compounds  In the
 mlcronucleus test.  Prog. Hut. Res.  1:  705-711.

 Tuazon, E.C.. W.P.L.  Carter, A.M.  Miner  and  J.N.  Pitts, Jr.   1981.  Reaction
 of hydrazlnes  with ozone  under simulated atmospheric  conditions.   Environ.
 Scl.  Techno1.  15: 823-828.

 U.S.   EPA.  1980.   Guidelines   and Methodology  Used  In  the  Preparation  of
 Health  Effect  Assessment   Chapters  of  the  Consent   Decree  Water  Criteria
 Documents.  Federal Register.  45(231):  79347-79357.

 U.S.  EPA.  1984a.  Methodology  and Guidelines  for  Ranking Chemicals  Based  on
 Chronic Tox1c1ty  Data.   Prepared  by  the Office of Health and  Environmental
 Assessment, Environmental  Criteria and  Assessment  Office, Cincinnati.  OH for
 the Office of Emergency and Remedial  Response, Washington, DC.
U.S.  EPA.   1984b.   Health  and  Environmental  Effects Profile  for  Hydrazlne
and Hydrazlne  Sulfate.   Prepared by  the  Office of Health  and  Environmental
Assessment, Environmental Criteria  and  Assessment  Office,  Cincinnati,  OH for
the Office of Solid Haste, Washington. DC.
0331 d
10-18
08/09/90

-------
U.S.  EPA.   1985.   Reportable  Quantity Document for  Hydrazlne  and Hydrazlne
Sulfate.   Prepared by  the  Office  of  Health  and  Environmental  Assessment,
Environmental  Criteria  and Assessment Office,  Cincinnati,  OH  for  the Office
of Emergency and Remedial Response, Washington, DC.

U.S.  EPA.   1986a.  Methodology for  Evaluating Reportable  Quantity  Adjust-
ments Pursuant  to  CERCLA  Section  102.   Prepared by the Carcinogen Assessment
Group,  Office  of   Health  and  Environmental  Assessment  for  the  Office  of
Emergency and Remedial Response, Washington. DC.

U.S.  EPA.   1986b.  Reference  Values  for  Risk  Assessment.   Prepared  by  the
Office  of  Health  and Environmental  Assessment,  Environmental Criteria  and
Assessment Office,  Cincinnati,  OH for  the  Office  of Solid Waste,  Washington,
DC.

U.S.  EPA.    1986c.   Guidelines  for   Carcinogen   Risk  Assessment.   Federal
Register.  51(185): 33992-34003.

U.S.  EPA.   1988.   Evaluation  of  the Potential CareInogenlcity of Hydrazlne
In  Support  of  Reportable  Quantity Adjustments  Pursuant to  CERCLA  Section
102.   Prepared  by the Carcinogen  Assessment  Group, Office  of   Health  and
Environmental  Assessment  for the Office of Emergency and Remedial Response,
Washington, DC.

U.S.  EPA.    1989.   Integrated  Risk  Information  System  (IRIS).   Online.
Office  of  Health  and Environmental  Assessment.  Environmental Criteria  and
Assessment Office,  Cincinnati, OH.

0331 d                               10-19                            08/09/90

-------
 U.S.  EPA/OWRS (U.S. Environmental Protection Agency/Office  of  Water  Regula-
 tions  and  Standards).   1986.   Guidelines  for  Deriving Numerical  National
 Water  Quality Criteria  for the  Protection  of  Aquatic  Organisms and  Their
 Uses.  U.S. EPA, Washington, DC.  p. 22-58, 98.  NTIS PB85-2270049/XAB.

 Vernot, E.H.,  J.D.  MacEwen,  R.H.  Bruner,  et  al.   1985.   Long-term Inhalation
 tox1c1ty of hydrazlne.  Fund. Appl. Toxlcol.   5:  1050-1064.

 Vljaykumar,  N.K.  and H.K.  Jain.   1979.   Comparative   studies  on  Induced
 mutations  with physical and chemical  mutagens  In  Drosophlla  roelanogaster:
 Part  1.  Specificity  and  spectrum  of  mutations.   Ind.   J.  Exp.  Blol.   17:
 61-65.

 Von  Wright,  A.   1981.   Hydrazlne and  methylhydrazlne  as  recA*  Independent
mutagens In EscheMchla  coll.   In:  Chromosome Damage and Repair,  E.  Seeberg
and  K.  Kleppe, Ed.   Plenum Press, NY.   p.  517-520.  NATO  Adv.  Study  Inst.
 Sen. A, 40.

Wade, D.R., P.H.  Lohman, E.I.  Mattern  and F. Berends.   1981.   MutagenlcHy
of  isonlazld  in Salmonella  and Us effects  on  DNA repair   and synthesis  In
human flbroblasts.  Nutat.  Res.  89: 9-20.

Hakabayashl.  T.,  H.  Hor1uch1. M.  Sokaguchl. et  al.   1983.   Induction  of
megamltochondria  1n  the mouse and  rat  livers  by hydrazlne.   Exp.   Nol.
Pathol.  39(2): 139-153.
0331 d
10-20
08/09/90

-------
 Hakabayashl,  T.,  K. Yamashlta, K. Adachl, et al.  1987.  Changes In physico-
 chemical  properties of mitochondria!  membranes  during the formation process
 of  megamltochondrla Induced by hydrazlne.  Toxlcol. Appl. Pharmacol.  67(2):
 235-248.

 Maid,  N.J.   1985.  Hydrazlne:  Ep1dem1olog1cal   evidence.   IARC  Sc1.  Publ.
 Iss. 65.   p.  75-80.

 Weast,  R.C.,   Ed.   1985.    CRC  Handbook of  Chemistry  and Physics,  66th  ed.
 CRC  Press,  Boca Raton, PL.  p. B-99, C-313.

 Weatherby,  J.H. and A.S.  Yard.   1955.   Observations on the subacute toxldty
 of hydrazlne.  Arch. Ind. Health.  11:  413-419.

 Wheeler,  C.E.,  S.R. Penn  and E.P. Cawley.   1965.   Dermatitis  from hydrazlne
 hydrobromlde  solder  flux.   Arch.  Dermatol.  91: 235-239.

 Wlndholz,  M.. Ed.   1983.   The  Merck   Index:  An  Encyclopedia  of  Chemicals,
 Drugs, and  B1olog1ca1s, 10th  ed.   Merck and Co.,  Inc., Rahway, NJ.  p.  473.
 691, 872.

 Hrangsjo,  K.  and  A. Martensson.  1986.   Hydrazlne contact dermatitis  from
 gold plating.  Contact Derm.  15(4):  244-245.  (Taken from NIOSH/00166309)

 Wryobek,  A.,   L.  Gordon and  G.  Watchmaker.   1981.   Effect  of 17  chemical
 agents Including  6 carclnogen/noncardnogen pairs  on  sperm  shape  abnormali-
 ties In  mice.  Prog. Mutat.  Res.  1(Eva1. Short-Term  Tests Carclnog.:  Rep.
 Int. Collab. Program): 712-717.
0331d                               10-21                            08/09/90

-------
 Yamamoto,  R.S.  and  J.H.  Uelsburger.   1970.   failure  of  arglnlne  glutamate  to
 Inhibit  lung  tumour  formation  by 1son1az1d  and  hydrazlne  1n mice.   Life Scl.
 9: 285-289.

 Yaws,  C.L.,  J.R.  Hooper  and  M.G.   Rojas.   1974.   Ammonia  and  hydrazlne.
 Chem. Eng.  81: 91-100.

 Yoon, J.S.,  J.H.  Mason,  R. Valencia, R.C.  Woodruff  and S.  Z1mmer1ng.   1985.
 Chemical  mutagenesls  testing  1n  DrosophHa.   IV. Results  of 45  coded com-
 pounds  tested for the  National  Toxicology Program.  Environ. Nol.  Mutagen.
 7: 349-367.
0331 d
10-22
08/09/90

-------
                                  APPENDIX A

                              LITERATURE SEARCHED



    This   HEED   Is  based  on  data   Identified  by  computerized  literature

 searches of  the  following:


              CHEHLINE
              TSCATS
              CASR online  (U.S. EPA Chemical Activities Status Report)
              TOXLINE
              TOXLIT
              TOXLIT 65
              RTECS
              OHM TADS
              STORET
              SRC Environmental Fate  Data Bases
              SANSS
              AQUIRE
              TSCAPP
              NTIS
              Federal Register
              CAS ONLINE (Chemistry and Aquatic)
              HSDB
              SCISEARCH
              Federal Research In Progress


These  searches  were  conducted 1n  July,  1989,  and  the  following  secondary

sources were reviewed:
    ACGIH  (American  Conference of  Governmental  Industrial  Hyglenlsts).
    1986.   Documentation  of  the  Threshold Limit  Values  and Biological
    Exposure Indices, 5th ed.  Cincinnati, OH.

    ACGIH  (American  Conference of  Governmental  Industrial  Hyglenlsts).
    1987.   TLVs:  Threshold Limit Values  for  Chemical  Substances  In the
    Work   Environment   adopted  by   ACGIH  with  Intended  Changes  for
    1987-1988.  Cincinnati, OH.  114 p.

    Clayton.  6.0.  and F.E.   Clayton,  Ed.   1981.   Patty's  Industrial
    Hygiene  and  Toxicology,  3rd rev.  ed.,  Vol.  2A.   John Wiley and
    Sons, NY.  2878 p.

    Clayton,  G.D.  and F.E.   Clayton,  Ed.   1981.   Patty's  Industrial
    Hygiene  and  Toxicology,  3rd rev.  ed..  Vol.  28.   John Wiley and
    Sons, NY.  p. 2879-3816.
0332d                               A-l                              01/22/90

-------
     Clayton,  G.D.  and  F.E.   Clayton,  Ed.   1982.   Patty's  Industrial
     Hygiene  and  Toxicology,  3rd  rev,  ed.,  Vol.  2C.   John Wiley  and
     Sons,  NY.   p.  3817-5112.

     Grayson,  N. and  D.  Eckroth, Ed.   1978-1984.   Klrk-Othmer  Encyclo-
     pedia  of  Chemical  Technology,  3rd  ed.   John Wiley and Sons, NY.  23
     Volumes.

     Hamilton, A.  and  H.L.  Hardy.  1974.  Industrial  Toxicology, 3rd ed.
     Publishing  Sciences Group, Inc., Littleton, MA.  575 p.

     IARC  (International  Agency  for  Research  on  Cancer).   IARC  Mono-
     graphs  on  the Evaluation  of  Carcinogenic  Risk  of Chemicals  to
     Humans.  IARC, WHO, Lyons, France.

     Jaber,  H.M.,  W.R.  Mabey,  A.T.  L1eu,  T.W.  Chou  and  H.L.  Johnson.
     1984.   Data   acquisition   for   environmental   transport  and  fate
     screening for  compounds of  Interest  to  the Office  of Solid  Waste.
     EPA  600/6-84-010.   NTIS  PB84-243906.   SRI  International,   MenTo
     Park, CA.

     NTP  (National  Toxicology  Program).  1987.   Toxicology Research and
     Testing  Program.   Chemicals   on   Standard  Protocol.   Management
     Status.

     Ouellette,  R.P.   and   J.A.   King.   1977.   Chemical Week  Pesticide
     Register.  McGraw-Hill Book Co., NY.

     Sax, I.N.   1984.   Dangerous  Properties of Industrial Materials, 6th
     ed.  Van Nostrand Relnhold Co., NY.

     SRI  (Stanford Research  Institute).   1987.   Directory  of  Chemical
     Producers.  Menlo Park, CA.

     U.S. EPA.   1986.    Report  on  Status  Report  In  the  Special  Review
     Program,  Registration  Standards  Program  and  the  Data  Call  In
     Programs.   Registration Standards  and the  Data  Call  In Programs.
     Office of Pesticide Programs, Washington, DC.

     USITC  (U.S.  International  Trade  Commission).    1986.   Synthetic
     Organic Chemicals.   U.S.   Production  and  Sales,  1985,  USITC  Publ.
     1892, Washington.  DC.

     Verschueren,  K.   1983.  Handbook  of  Environmental  Data  on Organic
     Chemicals, 2nd ed.  Van Nostrand Relnhold Co., NY.

    Wlndholz. M.t Ed.  1983.   The Merck Index,'10th  ed.  Merck and Co.,
     Inc., Rahway, NJ.

    Worthing, C.R.  and S.B. Walker,  Ed.   1983.  The  Pesticide Manual.
    British Crop Protection Council.  695 p.
0332d
A-2
01/22/90

-------
     In  addition, approximately  30 compendia  of  aquatic  toxicity  data were

 reviewed,  Including  the  following:


     Battelle's  Columbus  Laboratories.    1971.   Water  Quality Criteria
     Data   Book.   Volume  3.  Effects  of  Chemicals  on   Aquatic  Life.
     Selected  Data from  the  Literature  through 1968.   Prepared for the
     U.S. EPA under Contract No. 68-01-0007.  Washington, DC.

     Johnson,  W.W.  and M.T.  Flnley.   1980.  Handbook  of  Acute Toxicity
     of  Chemicals  to  Fish  and  Aquatic   Invertebrates.   Summaries  of
     Toxicity  Tests   Conducted  at  Columbia National  Fisheries Research
     Laboratory.   1965-1978.   U.S. Dept.  Interior,  Fish and Wildlife
     Serv.  Res. Publ. 137, Washington, DC.

     HcKee,  J.E.  and  H.W. Wolf.  1963.  Water  Quality  Criteria, 2nd ed.
     Prepared  for  the  Resources  Agency  of  California,  State  Water
     Quality Control  Board.  Publ.  No. 3-A.

     Plmental, D.  1971.   Ecological  Effects  of Pesticides on Non-Target
     Species.  Prepared for the U.S. EPA, Washington, DC.  PB-269605.

     Schneider, 8.A.   1979.   Toxicology  Handbook.   Mammalian  and Aquatic
     Data.   Book  1: Toxicology  Data.   Office  of Pesticide Programs, U.S.
     EPA, Washington, DC.  EPA 540/9-79-003.  NTIS PB 80-196876.
0332d                               A-3                              01/22/90

-------

-------















o>
^


*o
i
OB *
2 °"
c: **"
Z 4)
* i
< H-
^^
er*
3
fi
»
€f±
V?































o>
u
c
0)
L-
O>
MUD*
O)
oe

CT
O
0
ae.



^
o
01
V4-
UJ








O)
U.
a
VI
O
Q.
X
UJ





I/I
01
^
O)
CO

















co
0^
fMV

C -
Ol •
UJ TO
U
^f -•** M AJ
^*» ^i» *9 ^"™
Z Z Z 0)
^

i— O>
o o E
1
o
c
u
u
* • o
>» c
*J 0>
11
i/« 0>
^3 ^3 (Q "O
I— < t— • C 4V

O
u-

p
f^
Q.

O

lJj^ (/J
^^
* ^^
O C
•— B

C3 ^3 * ^^
« •-, 0^-


^J
0 0 «
1— 1 1— 1 l_


09
^
a
t^
o >»
Q^j
*"
X T- 0»
UJ O L.
c u e 1/1
Of- 41 O
••- c o) a
i-> 0 W 0 X
r- J= "c »-

Q Q E







1
Q.
O O O)
I— I I— I .C
_. ^^
* ^s
• rO  O
1-1 M 0 P- 3 •— •—

4>
a >»
a a o •*-> >»
*** *"* E "o *•
CO *- «J
UJ X «-
t-t O C
t— -M 41
•-I O»
h- w 0
>t Z •*- C
i- 3 O U
U O I- t-
U C K*J O W
i- 41 —1
c a> oo c c
o u o < o o
^ f^ C ^
jc e »- ae •« v
U O U O O) 41
ja «_ L. a. to vi
a f (Q i uj IQ •«
 (_> cj i oe ea CB





























^
^rf

^
^•*
t^v
*5
c
*~
u

K-l

• «
41
r~
^3
fQ
U
,—
a.
Q.
ff}

rih^
o
n

^c
z
0332d
B-l
01/22/90

-------

-------
                                  APPENDIX C
        DOSE/DURATION RESPONSE GRAPHS FOR EXPOSURE TO BROHOCHLOROMETHANE
C.I.    DISCUSSION
    Dose/duration-response   graphs   for   Inhalation  exposure  to  hydrazlne
generated  by the method  of  Crockett et al.  (1985)  using the computer soft-
ware  by Durkln  and  Meylan (1989) developed under contract to ECAO-C1nc1nnat1
are  presented  1n   Figures  C-l   through  C-5.   Data used  to generate  these
graphs  are presented  In  Section C.2.   In the  generation of  these figures,
all responses  were classified as  adverse  (FEL, AEL or  LOAEL)  or nonadverse
(NOEL or NOAEL)  for plotting.   The ordlnate expresses  Inhalation exposure In
either  of  two ways.  In Figures  C-l and C-2, the experimental concentration,
expressed  as mg/m3, was  multiplied by  the  time parameters  of  the exposure
protocol  (e.g.,  hours/day and days/week),  and  Is presented  as  the expanded
experimental  concentration  [expanded  exp  cone  (mg/m3)].   In  Figures  C-3
and  C-4,  the  expanded  experimental  concentration  was  multiplied  by  the
animal  Inhalation  rate  In  mVday and divided  by the animal body  weight in
kg  to calculate a  dally  dose  In mg/kg/day.  The dally  dose  was  then multi-
plied  by  the  cube  root  of  the ratio  of the  animal:human  body  weight to
adjust  for species differences  In metabolic rate  (Mantel and  Schneiderman,
1975).   The result  was multiplied  by  an  absorption  coefficient of  0.5 to
adjust  to  an  equivalent  absorbed  dose  and  then multiplied by  70  kg,  the
reference  human  body  weight, to express the  human  equivalent dose as rag/day
for a 70 kg human [human equivalent dose (mg/day)].
                                              j.
    The  adverse  effects  boundary  (solid line)  Is  drawn by  Identifying  the
lowest  adverse  effect  dose or  concentration  at the  shortest  duration of
exposure at  which  an adverse effect occurred.   From this starting point, an
Infinite line  1s extended upward,  parallel  to  the  dose axis.   The starting

0333d                                C-l                              01/22/90

-------
           1000
      C!

      \
     u
     ft
     a-
     x
     Q
     Z
    HVDINH.D2
    fInhalation Exposure)
     0.01                   0.1
HUHRN EQUIU MIMTION (fraction lifespan)

          ENVELOP NETHOO
 Key:    F « PEL
        I «= LOAEl
        N - NOEL
        Solid line - Adverse Effects Boundary
        Dashed line * No Adverse Effects Boundary
                                   FIGURE C-l

      Dose/Duration-Response Graph for Inhalation  Exposure to Hydrazlne:
             Envelope Method (Expanded Experimental Concentration)
0333d
       C-2
                                                                       01/22/90

-------

  I
  \

  :
  V

  L'

  M
  g
  «
  m
  x
 r
       e.ei
          e.eei
 (Inhalation Exposure)
     e.ei                  e.i
HUHflN EOU1U DURATION (fraction lifespan)

     CENSORED DftTfl METHOD
  Key:   F « PEL
         L - LOAEL
         N • NOEL
         Solid  line - Adverse Effects Boundary
         Dashed line • No Adverse Effects Boundary
                                   FIGURE  C-2

      Dose/Duration-Response Graph for  Inhalation Exposure to Hydrazlne:
          Censored Data Method (Expanded  Experimental Concentration)
0333d
          C-3
01/22/90

-------
         18068
     I
     J

     f
    c
    £

    :
   HYDINH.D2
   < Inhalation Exposure)
     e.ei                   0.1
HUHflN EQUIU DURRTION (fraction lifespan)
          EMUELOP ffilHOD
   Key:   F - FEl
          L « LOAEL
          N « NOEL
          Solid  line  *  Adverse Effects Boundary
          Dashed Hne • No Adverse Effects Boundary
                                   FIGURE C-3

      Dose/Ouratlon-Response Graph for Inhalation  Exposure to Hydrazlne:
                    Envelope Method  (Human Equivalent Dose)
0333d
        C-4
01/22/90

-------
       It
       it
      I

      *
            teeee F
            teee-r
               e.eei
      KMIH.'illft'

      < Inhalation Exposure)
HUKffl EOUIU DUJWIION (Fraction lifcspan)

     CENSORED DflTfl METHOD
  Key:    F = FEL
         L - LOAEL
         N * NOEL
         Solid line  •  Adverse Effects Boundary
         Dashed line * No Adverse Effects  Boundary
                                    FIGURE C-4

       Dose/Duration-Response  Graph for Inhalation Exposure to Hydrazlne
                  Censored  Data Method (Human  Equivalent Dose)
0333d
       C-5
01/22/90

-------
       e
       t
       \
       9
            IBM-:
               F3
                                                 F2
                                                            Ft
                i
       HVDORRL 02
    0.001
    I
Exposure)
     0.01                 0.1
HUHRN EQUHJ DUHIIION (fraction lifespan)

         ENUEOP HETHOD
 Key:   F -  PEL
        A -  ACl
        Solid  line « Adverse Effects Boundary
        Dashed line - No Adverse Effects  Boundary
0333d
                                   FIGURE  C-5

         Dose/Duration-Response Graph  for Oral  Exposure to Hydrazlne:
                    Envelope Method (Human Equivalent  Dose)
      C-6                               01/22/90

-------
 point  Is then  connected  to the lowest  adverse  effect dose or concentration
 at  the next  longer  duration of exposure that has  an  adverse effect dose or
 concentration equal  to or  lower   than  the  previous  one.  This  process Is
 continued  to  the  lowest  adverse  effect dose  or  concentration.   From  this
 point,  a line  parallel to  the  duration axis Is  extended Infinitely to the
 right.   The  adverse  effects  region  lies  above the  adverse  effects boundary.
    Using the envelope method,  the  no adverse effects boundary (dashed line)
 Is  drawn,  starting  with  the   point  representing  the  highest  no  adverse
 effects  dose  or  concentration.   From  this  point, a  line parallel  to  the
 duration  axis Is extended  to  the  dose  or  concentration  axis.  The starting
 point  Is  then connected to the next equal or lower no adverse effect dose or
 concentration at  a  longer  duration of  exposure.   When this  process  can no
 longer  be continued,  a line parallel  to  the dose or  concentration  axis 1s
 dropped  to  the duration axis.   The  no adverse  effects region lies below the
 no  adverse  effects  boundary.   At  either  ends  of  the  graph between  the
 adverse  effects  and no adverse  effects  boundaries  are regions of ambiguity.
 The area  (If any)  resulting from Intersections  of the adverse effects and no
 adverse effects boundaries  1s defined  as the region of contradiction.
    In  the censored  data  method, all no adverse effect points located In the
 region  of  contradiction are dropped from consideration,   and  the  no adverse
 effects  boundary  Is  redrawn   so  that  It  does  not  Intersect the  adverse
 effects  boundary  and no  region  of  contradiction  1s generated.   This method
 results  In the most  conservative definition of the no adverse effects region.
 In  Figures   C-1  through C-4,  the  adverse  effects boundary  (solid  line) Is
 defined  by  data  points  corresponding  to  LC5Q  values  In rats  (Rec.  |19),
 and mice (Rec.  #18) and  LOAELs for  lung  and  liver  effects  1n  dogs  (Rec.
 #13),  for  fatty  liver degeneration  In monkeys  (Rec.  #5), for  growth rate
0333d                               C-7                              01/22/90

-------
 depression  In  rats  (Rec.  #4),  for  amyloldosls  and  testlcular  effects  In
 hamsters  (Rec.  114), and  for  lung effects  In  rats  (Rec.  #15).  Rec.  #1,  a
 PEL  for mortality  In  mice, Is  not  displayed  because It would  obscure Rec.
 #4.   The  no adverse effects boundaries  (dashed line)  In Figures  C-1  and C-3
 are  defined by NOELs  In  dogs  examined  for  changes  1n  body weight, clinical
 chemistry,  hematology,  organ weight  and histology  (Recs.  #2  and  17).  and a
 NOEL  In female mice  examined  for effects  on  body weight  and pulmonary and
 liver   toxlcity  (MacEwen  et  al.,   1981)  (Rec.  #16).    A   small   region  of
 ambiguity  Is  evident   1n   graphs  produced  by  the  envelope  method  and  Is
 primarily  the result of  the NOEL In  mice (Rec.  #16),  suggesting  that mice
 may  be  less  sensitive  than  hamsters   and  rats  to  Inhalation exposure  to
 hydrazlne.
    Figures  C-2 and C-4  were generated with  the  censored data  method and
 show the most conservative definition of the no adverse effects region.
    Oral  nonneoplastlc  toxlclty  data  for  hydrazlne were  used  to generate
 Figure  C-5.  Two  oral  studies  were available  for  presentation 1n  dose/
 duration-response graphs:  Heatherby  and  Yard (1955)  and Blanclflorl (1970d).
 Neither  study  reported a NOEL  or   NOAEL,  and  only  serious effects  were
 observed, Including mortality  or shortened llfespan.  Lack  of NOEL or NOAEL
 data points precludes the generation of  a no adverse effects boundary.
 C.2.   DATA USED TO GENERATE DOSE/DURATION-RESPOUSE GRAPHS
C.2.1.   Inhalation.
Chemical Na*e:    Hydrazlne
CAS Number:       302-01-2
 Document Title:   Health and Environmental Effects Document on Hydrazlne
 Document Number:  pending
 Document Date:    pending
 Document Type:    HEED
0333d
C-8
01/22/90

-------
 RECORD  #1:
Comment:
 Species:
 Sex:
 Effect:
 Route:
Mice
Female
FEL
Inhalation
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Weight:
Inhalation hours/day:
Inhalation days/week:
# Inhal. Exp. days:
0.03 kg
0.2 ppm
0.262 mg/m"
6 months
6 months
32.00
24.00
7.00
180.00
Citation:
Number Exposed:     40
Number Responses:   1
Type of Effect:     DEATH
Site of Effect:     BODY
Severity Effect:    10

Exposed to  0,  0.2,  1  ppm continuously  or  1  or 5  ppm 6 hours/
day,  5 days/week  for  6  months.   Mortality was  dose-related,
none   In  controls;   no  statistical   analysis.   Death  due  to
hepatotoxlclty.

Haun and Klnkead, 1973
RECORD #2: Species:
Sex:
Effect:
Route:





Dogs
Hale
NOEL
Inhalation





Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Weight:
Inhalation hours/day:
Inhalation days/week:
# Inhal. Exp. days:
12.7 kg
1 ppm
0.234 mg/m*
6 months
6 months
32.00
6.00
5.00
130.00
Comment:


Citation:
Number Exposed:     8
Number Responses:   0
Type of Effect:
Site of Effect:
Severity Effect:    2

Exposed  to  0.2  or  1  ppm continuously  or  1 or  5  ppm  Inter
mlttently (see previous record).

Haun and Klnkead, 1973
0333d
                     C-9
                                           01/22/90

-------
 RECORD #3:
Comment:


Citation:
Species:
Sex:
Effect:
Route:
Dogs
Hale
LOAEL
Inhalation
               Number Exposed:
               Number Responses:
               Type of Effect:
               Site of Effect:
               Severity Effect:
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Weight:
Inhalation hours/day:
Inhalation days/week:
# Inhal. Exp. days:
                    8      8
                    NR     NR
                    WGTDC  HEMAT
                    BODY   BLOOD
                    4      3
12.7 kg
5 ppm
1.17 mg/m»
6 months
6 months
32.00
6.00
5.00
180.00
See  previous   records;   effects  were   reported   at  1  ppm
continuous and 5 ppm Intermittent.

Haun and Klnkead, 1973
RECORD #4: Species:
Sex:
Effect:
Route:





Rats
Male
LOAEL
Inhalation





Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Weight:
Inhalation hours/day:
Inhalation days/week:
f Inhal. Exp. days:
0.35 kg
1 ppm
0.234 mg/rn"
6 months
6 months
32.00
6.00
5.00
180.00
Comment:

Citation:
Number Exposed:     50
Number Responses:   NR
Type of Effect:     WGTDC
Site of Effect:     BODY
Severity Effect:    4

See record 11; dose-related growth rate depression.

Haun and Klnkead, 1973
0333d
                     C-10
                                           01/22/90

-------
 RECORD #5;
Comment:

Citation:
Species:
Sex:
Effect:
Route:
Honkeys
Female
LOAEL
Inhalation
Number Exposed:     4
Number Responses:   NR
Type of Effect:     PATHO
Site of Effect:     LIVER
Severity Effect:    5

See record #1.

Haun and Klnkead, 1973
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Weight:
Inhalation hours/day;
Inhalation days/week:
# Inhal. Exp. days:
8 kg
1 ppm
0.234 mg/m3
6 months
6 months
32.00
6.00
5.00
180.00
RECORD #6: Species:
Sex:
Effect:
Route:





Dogs
NR
LOAEL
Inhalation





Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Weight:
Inhalation hours/day:
Inhalation days/week:
# Inhal. Exp. days:
12.7 kg
4.6 ppm
1.08 mg/m3
31 Weeks
31 Weeks
32.00
6.00
5.00
217.00
Comment:
Citation:
Number Exposed:     2      2
Number Responses:   2      2
Type of Effect:     WGTDC  DEGEN
SHe of Effect:     BODY   LUNG
Severity Effect:    4      7

Exposed  0,  4.6  ppm;  one  dog  served  as a  control.   Muscle
tremors, weakness,  vomiting after  11  weeks.  Lung:  emphysema
and atalectasls.

Corns lock et al., 1952
0333d
                     C-ll
                                           01/22/90

-------
 RECORD #7:
Comment:


Citation:
Species:
Sex:
Effect:
Route:
Rats
NR
PEL
Inhalation
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Weight:
Inhalation hours/day:
Inhalation days/week:
I Inhal. Exp. days:
0.35 kg
4.6 ppm
1.08 mg/m3
31 weeks
31 weeks
32.00
6.00
5.00
217.00
Number Exposed:     20
Number Responses:   2
Type of Effect:     DEATH
Site of Effect:     BODY
Severity Effect:    1

Exposed 0,  4.6 ppm.   Ten  rats served  as  controls.
died during week 28; emphysema 1n lungs of  survivors.

Comstock et al., 1952
                                           Two  rats
RECORD #8: Species:
Sex:
Effect:
Route:





Rats
Male
PEL
Inhalation





Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Weight:
Inhalation hours/day:
Inhalation days/week:
I Inhal. Exp. days:
0.35 kg
13.7 ppm
3.2 mg/m3
6 months
6 months
32.00
6.00
5.00
180.00
Comment:


Citation:
Number Exposed:     30
Number Responses:   23
Type of Effect:     DEATH
SHe of Effect:     BODY
Severity Effect:    10

Only one  exposure  level; controls not  reported.   See Section
6.1.1.1 for description of results.

Comstock et al., 1954
0333d
                     C-12
                                           01/22/90

-------
 RECORD  #9:
Comment:


Citation:
Species:
Sex:
Effect:
Route:
Mice
Female
PEL
Inhalation
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Weight:
Inhalation hours/day:
Inhalation days/week;
# Inhal. Exp. days:
Number Exposed:     20
Number Responses:   15
Type of Effect:     DEATH
Site of Effect:     BODY
Severity Effect:    10

Only one  exposure level; controls not  reported
those surviving to term had no abnormalities.

Comstock et al.f 1954
0.03 kg
13.7 ppm
3.2 mg/m3
6 months
6 months
32.00
6.00
5.00
180.00
                                        Necropsy  on
RECORD #10: Species:
Sex:
Effect:
Route:





Guinea pigs
NR
PEL
Inhalation





Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Weight:
Inhalation hours/day:
Inhalation days/week:
# Inhal. Exp. days:
0.84 kg
13.7 ppm
3.2 mg/m'
6 months
6 months
32.00
6.00
5.00
180.00
Comment:

Citation:
Number Exposed:     10
Number Responses:   8
Type of Effect:     DEATH
SHe of Effect:     BODY
Severity Effect:    10

Only one exposure; controls not reported.

Comstock et al., 1954
0333d
                     C-13
                                           01/22/90

-------
 RECORD #11
Comment:


Citation:
Species:   Dogs            Body Weight:           12.7 kg
Sex:       Male            Reported Dose:         13.7 ppm
Effect:    PEL             Converted Dose:        3.2 mg/ma
Route:     Inhalation      Exposure Period:       6 months
                           Duration Observation:  6 months
                           Molecular Weight:      32.00
                           Inhalation hours/day:  6.00
                           Inhalation days/week:  5.00
                           # Inhal. Exp. days:    180.00

Number Exposed:     4
Number Responses:   2
Type of Effect:     DEATH
Site of Effect:     BODY
Severity Effect:    10

Only one  exposure;  controls not  reported.   Dogs surviving  to
term had fatty changes 1n liver, spleen.

Cornstock et al., 1954
RECORD #12: Species:
Sex:
Effect:
Route:





Guinea pigs
Male
LOAEL
Inhalation




•
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Weight:
Inhalation hours/day:
Inhalation days/week:
f Inhal. Exp. days:
0.84 kg
5.7 mg/m«
1.02 mg/ra*
10 weeks
10 weeks
32.00
6.00
5.00
70.00
Comment:


Citation:
Number Exposed:     8
Number Responses:   8
Type of Effect:     HYPRP
Site of Effect:     LUNG
Severity Effect:    7

0  or  3-6  mg/m»  for   2  weeks  and  4-8  mg/m9  additional  8
weeks (TWA 5.7 mg/m').

Ueatherby and Yard, 1955
0333d
                     C-14
01/22/90

-------
 RECORD  #13:
Comment:

Citation:
Species:
Sex:
Effect:
Route:
Dogs
NR
LOAEL
Inhalation
               Number Exposed:
               Number Responses:
               Type of Effect:
               SHe of Effect:
               Severity Effect:
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Weight:
Inhalation hours/day:
Inhalation days/week:
# Inhal. Exp. days:
                    2      2
                    2      2
                    PATHO  PATHO
                    LUNG   LIVER
                    7      5
Exposed to 3-6 (average 4.5 mg/m3).

Weatherby and Yard, 1955
 12.7 kg
 4.5 mg/m3
 1.07 mg/m3
 7 days
 7 days
 32.00
 6.00
 5.00
 7.00
RECORD #14:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Hamsters
Male
LOAEL
Inhalation
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Weight:
Inhalation hours/day;
Inhalation days/week:
# Inhal. Exp. days:
0.13 kg
0.25 ppm
0.0584 mg/m»
365 days
730 days
32.00
6.00
5.00
730.00
160
67
PATHO
LIVER
5
159
55
ATROP
TESTE
7
164
53
PATHO
KIDNY
5
117
20
PATHO
THYRD
5
155
49
PATHO
AORNL
5
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:

Exposed  0,  0.25,  1.0,  5.0  ppm   In  well   conducted,   well
controlled  study.   Increased  amalo1dos1s  of  liver,  kidney,
spleen, thyroid, adrenal; testlcular atrophy.

MacEwen et al., 1981
0333d
                     C-15
                                           01/22/90

-------
 RECORD #15;
Comment:
Species:
Sex:
Effect:
Route:
Rats
Hale
LOAEL
Inhalation
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Weight:
Inhalation hours/day;
Inhalation days/week;
# Inhal. Exp. days:
0.2 kg
0.05 ppm
0.0117 mg/m3
365 days
730 days
32.00
6.00
5.00
730.00
96
9
HYPRP
NASAL
3
95
42
HYPRP
PULMN
3
97
17
IRRIT
PULMN
3
100
NR
WGTDC
BODY
4
Citation:
               Number Exposed:
               Number Responses:
               Type of Effect:
               Site of Effect:
               Severity Effect:
Exposed 0, 0.05,  0.25,  1.0,  5.0 ppm.  Myocardlal degeneration
at 1.0  ppm in males, at  5.0 ppm 1n females.  Females  at  0.05
ppm  also  had   avarlan   atrophy,   salplngltls,   endometrltls,
reduced body weight.

MacEwen et al., 1981
RECORD #16: Species:
Sex:
Effect:
Route:





Nice
Female
NOEL
Inhalation





Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Weight:
Inhalation hours/day:
Inhalation days/week:
# Inhal. Exp. days:
0.024 kg
1 ppm
0.234 mg/m*
365 days
730 days
32.00
6.00
5.00
730.00
Comment:
Citation:
Number Exposed:     400
Number Responses:   0
Type of Effect:
SUe of Effect:
Severity Effect:    4

0,  0.05,  0.25,  1.0  ppm;  slight  dose-related
mortality,   but   probably  not  significant   (no
analysis).  No nonneoplastlc pathological lesions.

MacEwen «t al.. 1981
                                        Increase  In
                                         statistical
0333d
                     C-16
                                           01/22/90

-------
RECORD #17:
Comment:


Citation:
Species:
Sex:
Effect:
Route:
Oogs
Both
NOEL
Inhalation
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Weight:
Inhalation hours/day:
Inhalation days/week:
# Inhal. Exp. days:
Number Exposed:     8
Number Responses:   0
Type of Effect:
SHe of Effect:
Severity Effect:    2

Exposed 0,  0.25,  1.0  ppm; no  effects
chemistry, BSP retention,  pathology.

MacEwen et al., 1981
12.7 kg
1  ppm
0.234 mg/tn3
365 days
730 days
32.00
6.00
5.00
730.00
                             on  survival,  clinical
RECORD #18: Species:
Sex:
Effect:
Route:





Mice
NR
PEL
Inhalation





Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Weight:
Inhalation hours/day:
Inhalation days/week:
# Inhal. Exp. days:
0.03 kg
252 ppm
330 mg/m3
1 days
1 days
32.00
4.00
1.00
1.00
Comment:
Citation:
Number Exposed:     NR
Number Responses:   NR
Type of Effect:     DEATH
Site of Effect:     BODY
Severity Effect:    10

Acute  Inhalation  LCso for mice was  determined.   Not adjusted
to  equivalent  continuous exposure.   Pulmonary hemorrhage  and
edema, CNS hemorrhages due to convulsions.

Jacobson et al., 1955
0333d
                     C-17
                                           01/22/90

-------
 RECORD  #19:
Comment:
Citation:
 Species:   Rats            Body Weight:           0.35 kg
 Sex:       NR              Reported Dose:         570 ppm
 Effect:    PEL             Converted Dose:        747 mg/m3
 Route:     Inhalation      Exposure Period:       1 day
                           Duration Observation:  1 day
                           Molecular Weight:      32.00
                           Inhalation hours/day:  4.00
                           Inhalation days/week:  1.00
                           Jt Inhal. Exp. days:    1.00

 Number Exposed:     NR
 Number Responses:   NR
 Type of Effect:     DEATH
 Site of Effect:     BODY
 Severity Effect:    10

 Acute  Inhalation LC5Q  In rats  determined.   Not adjusted  to
 equivalent   continuous    exposure   concentration.    Pulmonary
 hemorrhage and edema, CNS hemorrhage due to convulsions.

 Jacobson et al., 1955
C.2.2.  Oral.

Chemical Name:
CAS Number:
Document Title:
Document Number:
Document Date  :
Document Type  :
   Hydrazlne
   302-01-2
   Health and Environmental Effects Document for Hydrazlne
   pending
   pending
   HEED
RECORD |1
Comment:
Citation:
Species:
Sex:
Effect:
Route:

Rats
Male
FEL
Water

Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
0.35 kg
100 mg/i


14.2 mg/kg/day
14 weeks
14 weeks


Number Exposed:     10
Number Responses:   3
Type of Effect:     DEATH
Site of Effect:     BODY
Severity Effect:    10

0, 0.1, 0.2,  0.5,  1 or 2 mg/mi  for  up to  14  weeks.   One rat
died after  5 weeks  exposure,  two died  after  6  weeks;  study
continued with survivors until 14 weeks.

Weatherby and Yard, 1955
0333d
                     C-18
01/22/90

-------
 RECORD  #2:
Comment:
Citation:
Comment:
Citation:
Comment:


Citation:
 Species:
 Sex:
 Effect:
 Route:
Rats
Male
FEL
Water
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
0.35 kg
500 mg/a
70.8 mg/kg/day
4 weeks
                                        Duration Observation: 14 weeks
Number Exposed:     10
Number Responses:   4
Type of Effect:     DEATH
Site of Effect:
Severity Effect:    10

See  record #1.   Dose  levels may  be  Inaccurate because  rats
did  not  tolerate drinking water hydrazlne concentrations well
at >500 mg/i.

Weatherby  and Yard, 1955
RECORD #3:




Species:
Sex:
Effect:
Route:

Rats
Male
FEL
Water

Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
0.35 kg
1000 mg/l
142 mg/kg/day
3 weeks
14 weeks
Number Exposed:     10
Number Responses:   1
Type of Effect:     DEATH
Site of Effect:
Severity Effect:    10

See record  #1.   Dose level  may  not be accurate  because rats
did not  tolerate drinking water  hydrazlne concentrations >500
mg/i.

Weatherby and Yard, 1955
RECORD #4:




Species:
Sex:
Effect:
Route:

Rats
Hale
FEL
Gavage

Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
0.35 kg
60 mg/kg/day
60 mg/kg/day
1 days
1 days
Number Exposed:     NR
Number Responses:   NR
Type of Effect:     DEATH
Site of Effect:
Severity Effect:    10

Acute  oral  1059 determination for  hydrazlne  In  young  rats
was ~60 mg/kg.

Weatherby and Yard. 1955
0333d
                     C-19
                                           01/22/90

-------
 RECORD  |5:
Comment:
Species:   Hamsters      Body Weight:
Sex:       Both          Reported Dose:
Effect:    FEL           Converted Dose:
Route:     Gavage        Exposure Period:
                         Duration Observation:

                            23
                            NR
                            SURVI
                            NR
                            10
0.14 kg
3 mg/kg/day
3 mg/kg/day
15 weeks
125 weeks
               Number Exposed:     23
               Number Responses:   14
               Type Of Effect:     DEGEN
               Site of Effect:     LIVER
               Severity Effect:    7
Citation:
Hamsters  received  0,  3 mg  hydrazlne  sulfate/day for 60  days
1n 15 weeks,  which Is equivalent to 0.42 mg  hydraz1ne/day  or
3.0   mg  hydrazlne/kg/day.   Liver   lesions   and   shortened
llfespan.

81anc1f1or1, 1970d
RECORD #6:



Species:
Sex:
Effect:
Route:
Hamsters
Both
FEL
Gavage
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
0.14 kg
3.5 mg/kg/day
3.5 mg/kg/day
20 weeks
Comment:
               Number Exposed:     35
               Number Responses:   29
               Type of Effect:     DEGEN
               Site of Effect:     LIVER
               Severity Effect:    7
                         Duration Observation: 125 weeks

                            35
                            NR
                            SURVI
                            BODY
                            10
Citation:
Hamsters  received  0,  2.8 mg  hydrazlne  sulfate/day  for  100
days In  20  weeks,  which  Is  equivalent  to 0.49 mg  hydrazlne/
day or  3.5  mg hydrazlne/kg/day.  Liver  lesions and shortened
Hfespan.

B1anc1MoM, 19700
NR = Not reported
0333d
                     C-20
       03/28/90

-------
            UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                     OFFICE OF RESEARCH AND DEVELOPMENT
                  ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
                               CINCINNATI. OHIO 45268
                                  AUG 25 1990
Health and Environmental Effects Document
                                   . o
W. Bruce Peirano
Acting Chief
Chemical Mixtures Assessment Branch

Matthew Straus
Chief, Waste Characterization Branch
Office of Solid Waste (OS-330)
SUBJECT:
FROM:
TO:
THRU:  fa Chris DeRosa, Ph.D.
         V  Acting Director
            Environmental Criteria and Assessment Office-Cin
                                  /, ///>/-"V
                                M/**«- V  ^-^
            William H. Farland, Ph.D.
            Director
            Office of Health and Environmental
               Assessment (RD-689)

      Attached  please  find  two  unbound  ccp'es  of  the  following  Health  and
Environmental Effects  Document (HEED) for:

      Hydrazine  (ECAO-Cin-G105)

      This document represents scientific summaries of the pertinent available data on
the environmental  fate and  mammalian and aquatic toxicity of the chemical  at an
extramural effort of about 14K. This document received internal OHEA, OPP and OTS
reviews as well  as review by two external  scientists.  Any pan of this document's  files
(e.g., drafts, references, reviews) are available to you upon request.

Attachments

cc:    K. Bruneske (OS-305) (w/attachments)
      M. Callahan (RD-689)
      P.  Durkin, Syracuse Research Corporation (w/attachments)
      S. Griffin (OS-330) (w/attachments)
      R. Hardesty (RD-689)
      M. Holland (RD-689)
      B. Hostage (OS-210) (w/attachments)
      A. McBride (OS-331)
      E. McNamara (PM-211A) (w/attachments)
                                                                            •

-------

-------
1
         cc:   J. Moore (RD-689)
               M Pfaff (RD-689) (w/attachmems)
               C Ris (RD-689)
               R. Scarberry (OS-330)

-------

-------