United States
        Environmental Protection                           '      tlAU-l IN-b IU J
        Agency                                          March, 1991
        Research  and
        Development
        HEALTH AND  ENVIRONMENTAL EFFECTS DOCUMENT
        FOR 2-NITROANILINE
       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                    DRAFT: DO NOT CITE OR QUOTE
j


                           NOTICE

i    This document 1s 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 Is  being circulated  for comments
on Its technical accuracy and policy Implications.
                                        HEADQUARTERS LIBRARY
                                        ENVIRONMENTAL PROTECTION AGEKtf
                                        WASHINGTON, D.C. 20460

-------

-------
                                  DISCLAIMER







    This report  Is  an external draft  for  review purposes only and  does  not



constitute  Agency  policy.   Mention  of  trade names  or commercial  products



does not constitute endorsement or recommendation for  use.
                                      11

-------
                                    PREFACE

     Health  and  Environmental Effects Documents (HEEDs) are  prepared  for  the
Office  of  Solid Waste and Emergency Response  (OSWER).  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  Office   files  are
evaluated  as  they  pertain  to  potential  human  health,
environmental   effects  of  hazardous  waste  constituents
searched  for   in  this document  and  the  dates   searched
aquatic  life  and
   The   literature
 are  Included  1n
"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  lifespan.   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  RfOs  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]*  (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 noncarcino-
genlc health effects  of compounds that are also carcinogenic.

    Reportable   quantities   (RQs)   based   on   both   chronic   toxlclty   and
carclnogenldty 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  toxlclty
and  carclnogenldty)  represent  two  of six  scores  developed,  (the  remaining
four reflect  ignltabllHy,  reactivity,  aquatic  toxlclty,  and  acute mammalian
toxlclty).   Chemical-specific  RQs   reflect  the lowest of  these  six  primary
criteria.   The  methodology  for  chronic  toxlclty and cancer  based RQs  are
defined in U.S. EPA,  1984 and  1986a, respectively.
                                      111

-------
                                          EXECUTIVE  SUMMARY

^             When  released  to the atmosphere, 2-nHroanlllne will  degrade  rapidly by
           reaction  with  photochemically produced  hydroxyl  radicals.   The  estimated
           half-life  for  this  reaction   In  air  Is  -11  hours  (Atkinson,  1988).   By
           analogy  to  the  aromatic amlne chemical  class  (Parris,  1980),  ?-n1troan1-
           llne  may  undergo  covalent   binding  to  humlc  materials  In  soil  and  water.
           This  covalent binding  process  may represent a  mechanism by which  2-nltro-
           anlllne  may  be  converted  to  a  latent  form  In  the biosphere.  If  covalent
           binding  does not occur, 2-n1troan1l1ne  may  leach readily In  soil,  based on
           estimated  K    values  of  53-79  {lyman,  1982;  Swann  et al.,  1983).   The
           results  of  various  biological  screening  studies  Indicate that 2-nHroanlllne
           resists  blodegradatlon  or  Is  only  slowly  blodegraded  (KHano, 1978;  Urano
           and Kato,  1986;  Young and Affleck,  1974;  PHter,  1976; Malaney,  1960;  Hallas
           and  Alexander,  1983;  Alexander  and  Lustlgman,  1966;   Zeyer  and  Kearney,
           1983).   Aquatic  hydrolysis  and volatilization are  not significant  breakdown
           processes.
               The  National Occupational  Exposure  Survey  (NOES)  estimated  that  1611
           U.S.  workers  are  potentially  exposed  to  2-nHroanlllne   (NIOSH,  1989).
           Occupational  exposure  to 2-n1troan1l1ne  U  possible  during Its  production
           and  use  as  a  chemical  Intermediate.  The most  likely route of exposure In
           occupational  settings  Is  by  dermal  contact.   Exposure from Inhalation  1s
           probably  low because nltroanlllne  Is  a  solid  at room  temperatures and  has
           low vapor  pressure  (NCI,  1985).  The use  of  2-nltroanlllne  In  dye  synthesis
           suggests  that  It  may be released to  the  environment  1n  wastewater  effluents
           from dye  production  (Steadman  et  al., 1977).  2-NHroanlllne may also  occur
           In  the  environment  as  a mlcroblal  decomposition product of  dlnltrobenzene
                                                 1v

-------
 (Hallas  and  Alexander,  1983).   Pertinent  monitoring  data  regarding  food.
 Inhalation  and dermal  exposure  of  2-n1troan1l1ne  were not  located  In  the
available literature cited In Appendix A.
    The  lack  of adequate  freshwater  and  saltwater  toxlclty  and bloconcentra-
tlon  data   for  flora and  fauna  precludes  the development  of criteria  for
2-nltroanlllne.  The larval  sea  lamprey  was  not affected when  exposed to 5.0
mg/2.  for  24  hours   (Applegate   et  a I.,  1957);   9.8  mg/i  was  the  14-day
LC5Q  for gupples  (Oeneer  et  al.,  1987).  Carp that  were  force-fed  2-nitro-
anlUne at  a  dose  <189  mg/kg suffered no observed  adverse  effects  (Loeb and
Kelly,  1963).   The dilate  bacteria,  Tetrahyjnena  pyrlformls.  had a  60-hour
IGC50  of   115.55  mg/B.   (Schultz  and   Applehans,   1985).   LD   s   for  the
redwing blackbird, starling,  coturnlx and house sparrow were 750,  >1000, 750
and 750 mg/kg, respectively (Schafer  et al.,  1983).
    Five hours after  IntraperHoneal  administration  of  2-n1troan1l1ne at 100
ymol/kg  (13.8  mg/kg)  to   male  Wlstar rats,   unspecified   dlazo-poslUve
metabolites were Identified  in  the urine (Uatanabe et  al.,  1976).   Although
there are few  data relevant  to  the absorption  of  2-n1troan1l1ne  (Moskalenko,
1966; Vasllenko et al.,  1974),  the similarity of  Us properties  to  those of
the  4-1somer, which  Is  known  to  be  rapidly  absorbed  when  administered
orally,  1ntraper1toneally  or  dermally  (U.S.  EPA,   1985),   suggests   that
2-nHroan1l1ne may also be  readily absorbed  when given by  these  routes.  If
the o-lsomer behaves similarly to  the  p-1somer, a  substantial  fraction  of an
Intraperltoneally  administered dose  of 2-nltroanlllne or Its metabolites may
be excreted In the urine (Mate et al., 1967).
    Two studies by  Bio/Dynamics  reported effects  In  rats  that were  exposed
by  Inhalation  to  vapor/aerosols  of  2-n1troan1l1ne  6 hours/day,  5  days/week
for 4 weeks.   In  the first  (Bio/Dynamics,  1983a),  2-n1troan1l1ne at 0, 10,

-------
28  or  73 mg/m3  mixed  with  2000  mg/m3  cellosolve was  given to  both  sexes;
in  the second  study  {B1o/Dynamics,  1983b),  rats  were  exposed to 0,  9.8 or  93
mg/m3  in  the  absence  of  cellosolve.   Secretory  effects   (nasal  discharge
and  lacrlmatlon)  were  reported In  the  first study at  >28  mg/m3 and  in  the
second  study  at  9.8   mg/m3.   At  73  and  93   mg/m3,  males  had  decreased
leukocyte  counts.   Females  showed  decreased   erythrocyte  and  hemoglobin
values and  higher  relative liver  weights  at 73  mg/m3.   Both  sexes  showed
altered  erythrocyte  morphology and  slight,  but  not  significantly,  elevated
methemoglobin   levels   at   73  mg/m3.    At  93   mg/m3,  methemoglobin  and
hematocrU Increased significantly.   Vasllenko et  al.,  (1974)  reported hemo-
toxlc  effects  from  5  mg/m3 2-n1troan1l1ne  given  5  hours/day for  4 months,
but  experimental  details were  lacking.   Moskalenko  (1966)  and  Vasllenko  et
al.  (1972)  also  reported  Increased  hemotoxlc effects  from  short-term  oral
intoxication.   Pertinent  data  regarding  chronic exposure  to  2-nUroanlline
by any route were not located.
    Acute  Intraperitoneal  or  oral  administration  of 2-nHroaniline  caused
hemotoxlc effects  (Watanabe et al.,  1976; Moskalenko, 1966).   Other effects
of  acute  oral  administration were  spasms,  enlarged  livers  and altered
oxidatlve phosphorylation  (Moskalenko,  1966;  Vasllenko et al.,  1974; Kolodub
and Vasllenko, 1976).  Topically applied as  a paste  In  water,  2-nHroaniline
was transiently  Irritating  to  the skin  and  eyes  of rabbits  (Younger Labora-
tories,  1977).   Acute   inhalation  exposure  to 7.5-11.7  mg/l  2-nHroanlllne
aerosol/vapor  for  4 hours  led to  mortalities   In  rats,  witti no  consistent
dose-response  trend (Haskell   Laboratories,  1981).    The  oral  LD_Q  values
for  rats,  mice and  guinea  pigs were 635-3520  mg/kg  (Younger  Laboratories,
1977;  Toxic  Substances  List,   1974;  RTECS,  1975;  Vasllenko  et al.,   1974;
Moskalenko,  1966).   The  dermal  LD™  for  rats  was  7940  mg/kg  (Younger
Laboratories, 1977).
                                      v1

-------
    Pertinent  data  regarding the cardnogenlctty of  2-n1troan1l1ne  adminis-
tered  orally  or by  Inhalation  or  other routes of exposure were  not  located
1n  the  literature  surveyed.   The  compound  was  predominantly  nonmutagenlc
(see  Section  6.3.).   In  developmental  toxlclty  studies,   2-n1troan1l1ne
caused maternal  toxldty  (plloerectlon, pale  or  cold  extremities,  depressed
weight  gain  and  food  consumption,  hypoactlvlty,  convulsions,  salivation,
prostration,  shallow  respiration,  loss of muscle coordination,  and  mortali-
ties) when  mated  rats  were given 300-1200 mg/kg  by  gavage  on gestation days
6-15  (Monsanto, 1984,  1985).   Mean  fetal body weights  were depressed at 800
and 1200 mg/kg.  One fetus  1n  each  of 2 of 25 litters of dams dosed  with 600
mg/kg  had  situs Inversus  syndrome.  No  fetal  effects  were reported  at  dose
levels below those associated with maternal toxlclty.
    2-N1troan1l1ne was placed  1n  EPA  welght-of-evidence Group D because data
were  not  located  regarding  Its  cardnogenlcHy  In  humans  or   animals.
Neither potency slope factors nor a  cancer-based RQ were derived.
    An RfC  of  0.002  mg/m3  for  subchronU  Inhalation  exposure was  derived
from  the  NOAEL of 9.8 mg/m3  1n the  4-week  Intermittent  exposure  Inhalation
study  by  Bio/Dynamics  (1983b).   A  NOAELucr  of 1.8  mg/m3  was  estimated
                                           Ht L
and  an  uncertainty  factor  of  1000  was  applied.    An  RfC  for   chronic
Inhalation  exposure  may  be extrapolated  from  these  data by dividing  the
subchronlc RfC  by an  additional uncertainty factor of  10,  giving a  value of
0.0002 mg/m3.   However, confidence 1n this RfC Is  low.
    Oral  data  were  not sufficient  to derive RfDs for  subchronlc or  chronic
oral  exposure  to  2-nltroanlllne.   In the absence of  adequate oral  data,  a
provisional RfD of 0.0006 mg/kg/day  for  subchronlc oral  exposure  was  derived
from  the  Inhalation   study  that  served  as   the  basis  for   the  subchronlc
Inhalation  RfC.   The provisional status  reflects low  confidence because of
                                      vll

-------
route-to-route  extrapolation.    An  RfD  for  chronic  oral  exposure  may  be
extrapolated Prom these data by  dividing  the  subchronic  RfD by an additional
uncertainty factor  of  10,  giving a  value of 0.00006  mg/kg/day.   Confidence
in both the subchronic and chronic oral RfD is low.
    Because data  for  2-nitroanlline  were  Inadequate for derivation of  an  RO,
for chronic toxicity,  the  RQ of 100 derived  by  U.S.  EPA (1985)  for  4-nitro-
aniline was adopted for  2-nitroaniline.   Short-term exposure data  indicate
that both isomers have similar  (hemotoxic) effects in animals.
                                     vlii

-------
                              TABLE  OF  CONTENTS
                                                                       Page
1.  INTRODUCTION	     1

    1.1.   S1RUCTURE AND CAS NUMBER	     1
    1.2.   PHYSICAL AND CHEMICAL PROPERTIES 	     1
    1.3.   PRODUCTION DATA	     2
    1.4.   USE DATA	     3
    1.5.   SUMMARY	     3

2.  ENVIRONMENTAL FATE AND TRANSPORT	     4

    2.1.   AIR	     4
    2.2.   WATER	     4

           2.2.1.    Hydrolysis	     4
           2.2.2.    Oxidation 	     4
           2.2.3.    Mlcrobial Degradation 	     5
           2.2.4.    Volatilization	     5
           2.2.5.    Adsorption	     5

    2.3.   SOIL	     6

           2.3.1.    Mlcrobial Degradation 	     6
           2.3.2.    Adsorption	     6

    2.4.   SUMMARY	     7

3.  EXPOSURE	     8

    3.1.   WATER	     8
    3.2.   FOOD	     9
    3.3.   INHALATION	     9
    3.4.   DERMAL	     9
    3.5.   SUMMARY	     9

4.  ENVIRONMENTAL  TOXICOLOGY	    11

    4.1.   AQUATIC TOXICOLOGY 	    11

           4.1.1.    Acute Toxic  Effects on Fauna	  .  .  .  .    11
           4.1.2.    Chronic  Effects  on Fauna	    11
           4.1.3.    Effects  on Flora	    11
           4.1.4.    Effects  on Bacteria 	    12

    4.2.   TERRESTRIAL TOXICOLOGY 	    12

           4.2.1.    Effects  on Fauna	    12
           4.2.2.    Effects  on Flora	    12
                                     Ix

-------
                          TABLE  OF  CONTENTS  (cont.)
    4.3.   FIELD STUDIES	   12
    4.4.   AQUATIC RISK ASSESSMENT	   12
    4.5.   SUMMARY	   13

5.  PHARMACOKINETCS	   15

    5.1.   ABSORPTION	   15
    5.2.   DISTRIBUTION	   15
    5.3.   METABOLISM	   15
    5.4.   EXCRETION	   15
    5.5.   SUMMARY	   16

6.  EFFECTS	   17

    6.1.   SYSTEMIC TOXICITY	   17

           6.1.1.   Inhalation Exposure 	   17
           6.1.2.   Oral Exposure	   19
           6.1.3.   Other Relevant Information	   19

    6.2.   CARCINOGENICITY	   21

           6.2.1.   Inhalation Exposure 	   21
           6.2.2.   Oral Exposure	   22
           6.2.3.   Other Relevant Information	   22

    6.3.   GENOTOXICITY	   22
    6.4.   DEVELOPMENTAL TOXICITY 	   22
    6.5.   OTHER REPRODUCTIVE  EFFECTS 	   25
    6.6.   SUMMARY	   26

7.  EXISTING GUIDELINES AND STANDARDS 	   28

    7.1.   HUMAN	   28
    7.2.   AQUATIC	   28

8.  RISK ASSESSMENT	   29

    8.1.   CARCINOGENICITY	   29

           8.1.1.   Inhalation	   29
           8.1.2.   Oral	   29
           8.1.3.   Other Routes	   29
           8.1.4.   Weight of  Evidence	   29
           8.1.5.   Quantitative Risk Estimates  	   29

    8.2.   SYSTEMIC TOXICITY	   29

           8.2.1.   Inhalation Exposure 	   29
           8.2.2.   Oral Exposure	   32

-------
                           TABLE  OF  CONTENTS  (cont.)
 9.  REPORTABLE QUANTITIES
     9.1.   BASED ON SYSTEMIC TOXICITY
     9.2.   BASED ON CARCINOGENICITY .
10.  REFERENCES.
APPENDIX A: LITERATURE SEARCHED	
APPENDIX B: SUMMARY TABLE FOR 2-NITROANILINE 	
APPENDIX C: DOSE/DURATION RESPONSE GRAPHS FOR EXPOSURE TO
            2-NITROANILINE 	
35
35

37

49
52

53
                                      xl

-------
                              LIST OF TABLES
No.                              TUIe                               Page
6-1     1050 Values  for  2-NHroanlHne	    20
6-2     Genotoxlclty Testing of 2-NHroan1l1ne	    23
9-1     2-N1troan1llne:  Minimum Effective Dose (MED) and
        Reportable Quar>tHy  (RQ)	    36
                                    xll

-------
                             LIST OF ABBREVIATIONS
ADI
AEL
ATP
BCF
BOD
CAS
COO
DNA
PEL
NEC
HID
IGC

Koc
K
 ow
LC
50
  50
LD
  50
LDU
LED
LOAEL
MM AD
NOAEL
PCB
pKa
RDOR
RfD
RQ
RVd
RVe
TWA
Acceptable dally Intake
Adverse-effect level
Adenoslne trlphosphate
Bloconcentratlon factor
Biological oxygen demand
Chemical Abstract Service
Chemical oxygen demand
Deoxyrlbonuclelc add
Frank-effect level
Human equivalent concentration
Highest Ineffective dose
Growth Inhibition concentration
Soil sorptlon coefficient
Octanol/water partition coefficient
Concentration lethal to 50% of recipients
Dose lethal  to 50% of recipients
Log dose units
Lowest effective dose
Lowest-observed-adverse-effect level
Mass median  aerodynamic diameter
No-observed-adverse-effect level
Polychlorlnated blphenyl
Negative 1og,Q of dissociation constant
Regional deposited  dose ratio
Reference dose
Reportable quantity
Dose-rating  value
Effect-rating value
Time-weighted average

-------
                               1.  INTRODUCTION



1.1.   STRUCTURE AND CAS NUMBER



    2-NHroan1l1ne 1s the  common  name  for  the  chemical  known as benzenamlne,



2-nltro- by  the CAS.   It  1s also  known  by  the   synonyms  o-n1troan1l1ne,



ortho-nltroanlHne, o-amlnonltrobenzene, 2-amlnonltrobenzene  and  ONA.   Trade



names  for  ?-n1troan1lIne  Include Azoene  Fast  Orange  GR  base  (and  salt),



Azoflx  Orange  GR  salt, Azogene  Fast  Orange  GR,  Azoic  Olazo Component  6,



Brentamlne  Fast Orange  Gr base  (and  salt),  C.I.  Azoic  Dlazo Component  6,



C.I.  37025,  Devol  Orange  B  (and  salt  B),  Dlazo Fast Orange  GR,  Fast  Orange



Base  GR  (and JR),  Fast Orange  0 base (and  salt),  Hlltonll Fast  Orange  GR



base  (and   salt),  Hlndasol  Orange  GR  salt,  Natasol  Fast  Orange  GR  salt,



Orange  Base  C1BA  IJ,  Orange  Base  1RGA II  and  Orange  GRS  salt  (Chemllne.



1989).   The  structure,   molecular weight,  empirical  formula and CAS  number



for 2-n1troan1l1ne are as  follows:
Molecular weight:  138.13



Empirical formula:  C,H,N000
                     b D c /-


CAS Registry nur er:   88-74-4



1.2.   PHYSICAL AND CHEMICAL PROPERTIES



    2-Nltroanlllne Is  an  orange-yellow,  orange-red or  gold-yellow  crystal-



line  compound  that   Is  soluble  In  alcohol,   ether,  benzene,  acetone  and



chloroform  {Weast,  1985; Wlndholz,  1983;  Hawley,  1981).   Selected  physical



properties are as follows:
0318d
-1-
01/17/90

-------
     Melting point;
     Boiling point:
     Specific gravity:
     Vapor pressure:
       at 25°C

     Water solubility:
       at 30°C
     Log Kow:
     pKa:
     Flash point:
     Autolgnltlon:
     Conversion factor;
       (air at 20°C)
71.5°C
284°C
1.442 (15°C)
0.000878 mm Hg
{extrapolated
 from 40°C)
1470 ppm
1.85
-0.26 (25°C)
168°C
521°C
1  mg/m3 = 0.174 ppm
1  ppm =5.74 mg/m3
Heast, 1985
Weast, 1985
Weast, 1985
Ferro and
Placente, 1985
Gross et al., 1933
Hansch and Leo, 1985
Perrln, 1964
Hawley, 1981
Hawley, 1981
    2-N1troan111ne  forms  water soluble  salts  with mineral  acids  (Wlndholz,
1983).
1.3.   PRODUCTION DATA
    In  1988,   three  U.S.  manufacturers  produced  8.366 million  pounds  of
2-n1troan1l1ne.   These  manufacturers   Include   OuPont,  Monsanto   and  the
Blackman-Ulmer  Division of  Synalloy  Corporation (USI1C,  1989).   The  1989
Directory of Chemical Producers cites  the Monsanto  Company  In  Sauget,  IL,  as
a manufacturer  of  2-nltroanlllne.   The  Blackman-Ulmer Division of  Synalloy
Corp.  Is  located  In  Spartanburg,  SC  (SRI,  1989).   The   dye  and  pigment
division of DuPont  1s located In Deepwater,  NJ.
    2-N1troan1l1ne  Is  manufactured  by  reacting  2-nltrochlorobenzene  with
aqua ammonia (Dunlap, 1981; Wooster, 1963).
0318d
        -2-
                 05/21/90

-------
 1.4.   USE DATA
    2-N1troanll1ne  1s  used as a  chemical  Intermediate to produce  a variety
 of  dyes,   lakes  and  toners  for  the dye  Industry  (Kuney,  1988;  Northcott,
 1978).  It  Is  also used as a  chemical  Intermediate to produce sulfaqulnoxa-
 line  (a  cocddlostat),  o-phenylenedlamlne,  benzotrlazole  and  photographic
 antifogging agents  (Kuney, 1988).
 1.5.   SUMMARY
    2-N1troan111ne  Is  an  orange-yellow,  orange-red or gold-yellow crystal-
 line  compound  that  Is  soluble  In  alcohol,  ether,  benzene,  acetone  and
 chloroform  (Weast,  1985;  'dindholz,  1983;  Hawley,  1981).   Its  solubility  In
 water at  30°C  Is 1470 ppm (Gross  et al.,  1933).  In  1988,  three  U.S.  manu-
 facturers  produced  8.366  million  pounds  of  2-nltroanlllne  (USITC,  1989).
 2-NHroanlllne  Is  used  as  a  chemical  Intermediate  to produce a  variety  of
 dyes, lakes and  toners for the dye  Industry  (Kuney,  1988;  Northcott,  1978).
 It  Is  also used  as a chemical  Intermediate to produce  sulfaqulnoxallne  (a
 coccldiostat),  o-phenylenedlamlne,   benzotrlazole  and   photographic   anti-
 fogging agents (Kuney, 1988).
0318d                               -3-                              01/17/90

-------
                     2.  ENVIRONMENTAL FATE AND TRANSPORT
2.1.   AIR
    Based on a  vapor  pressure  of  0.000878  mm Hg at 25°C (Ferro and Placente,
1985),  2-n1troan1l1ne  is expected  to  exist In  the  atmosphere predominantly
In  the  solid phase  {Elsenrelch et  al.t  1981).  The  dominant environmental
fate process  In  air  Is probably the gas-phase  reaction with sunlight-formed
hydroxyl  radicals.   Using  the method  of  Atkinson (1988),  the  rate constant
for  the  gas-phase reaction  between  2-nitroan1line and  hydroxyl  radicals  Is
an  estimated  34.3xlO~lz  cmVmolecule-sec  at   25°C.    Assuming  an  average
atmospheric  hydroxyl  radical  concentration  of  5xl05  molecules/cm3,  the
half-life for this reaction Is -11  hours.
2.2.   HATER
2.2.1.   Hydrolysis.    Pertinent  data  regarding the  hydrolysis  of  2-n1tro-
anlllne were  not located  In  the available  literature cited  in  Appendix  A.
However,  aromatic  nitro  compounds  and   aromatic  amines  generally  resist
aqueous environmental  hydrolysis (Harris,  1982).  Therefore,  hydrolysis  of
2-nitroanlline Is not expected to be significant In the environment.
2.2.2.   Oxidation.    Aromatic   amines  in  natural water  react  with  photo-
chemlcally  produced  oxidants  such as  hydroxyl  radicals and  peroxy radicals
(Mill  and  Mabey,  1985).   For  unsubstltuted  aniline,  the  half-lives  for
reaction with hydroxyl and peroxy radicals  are  -30 and 19 hours of sunlight.
respectively (Mill and Mabey,  1985).  These  half-lives pertain specifically
to  photo-oxidation  at  the  water's  surface  under constant,  full-intensity
sunlight.    Reaction  data  specific  to  2-n1troanil1ne  were  not  located.
Compared  with  aniline,  the  reaction  of  hydroxyl and peroxy  radicals  with
2-nltroaniline  is  probably  slower  because of  the nitro presence.  Although
0318d
-4-
02/15/91

-------
 specific  experlinental  or   estimated  rate  data  are   not  available.  U  1s
 possible  that  photo-oxidation  of 2-nltroanlllne  1n shallow,  brightly  sunlit
 natural water has some environmental significance.
 2.2.3.   Mlcroblal Degradation.   The  results  of  several  biological  screen-
 Ing  studies  Indicate  that  2-n1troanlUne  either  resists blodegradatlon  or  Is
 only  slowly  blodegraded   (KHano,  1978;  Urano  and  Kato,  1986;  Young and
 Affleck,   1974;    PHter,    1976;   Halaney,   1960).    For   example,    <30%
 bio-oxidation  was  observed  over  a   14-day  Incubation   period   using the
 Japanese M1TI protocol  (KHano,  1978).  LHtle or  zero degradation  was  found
 using  electrolytic  resplrometers (Urano  and  Kato,  1986;  Young and  Affleck,
 1974).   A  theoretl-  cal   BOD  of  only   16%  was measured   In   a Warburg
 resplrometer  using activated  sludge  that   had  been   acclimated  to aniline
 (Halaney,  1960).   Removal  was  0% (based  upon COD) In a  batch system  using
 activated sludge and a 5-day Incubation period (PHter, 1976).
    Aerobic  Incubation  of  2-nltroanlllne  In  a   rotary shaker  using  sewage
 Inocula  for  52 days  resulted  In a maximum loss of  15%,  as  measured  by  UV
 absorbance  (Hallas   and   Alexander,   1983).   Incubation   In   an   anaerobic
 Incubator  for  52  days resulted  1n  a  loss  of  -70 percent.   A  lag  period  of
 -17  days   occurred   before  anaerobic  loss  was  measurable  (Hallas  and
 Alexander, 1983).
 2.2.4.   Volatilization.  Based  upon a  water  solubility of 1470 ppm at  30°C
 and  a  vapor  pressure of  0.000878 mm  Hg  at  25°C (see  Section  1.2.), the
 Henry's   Law   constant   for   2-nHroanlllne  is   an  estimated   1.09xlO"7
 atm-m3/mol.   A  Henry's  Law  constant of   this   magnitude   Indicates   that
 volatilization from water  1s not significant (Thomas,  1982).
 2.2.5.   Adsorption.   Based  upon  the discussion  In Section 2.3.2.,  2-n1tro-
 anlUne may undergo strong  covalent  binding with humlc materials  In natural
water, resulting In chemical conversion of  2-nltroanlllne to a  latent  form.

0318d                               -5-                              05/21/90

-------
 The covalent binding reaction is not  readily  reversible.   In  the absence of
 covalent  binding,  adsorption to sediment and  suspended material  in  water is
 not expected to be  significant.
 2.3.    SOIL
 2.3.1.    Mlcroblal  Degradation.   Using  14C-radiolabeled   2-nltroaniline,  a
 20-day  14C-carbon  dioxide evolution of  1.9% was measured  from  a laboratory
 flask  system containing a  silt  loam soil medium  (Zeyer  and Kearney,  1983).
 From  the  same  soil  system that  had  been  sterilized  with  sodium  azlde,
 14C-carbon  dioxide  evolution  was  <0.3%.  Although  the rate  of  degradation
 is  slow,  these results suggest that 2-nHroaniline can biodegrade in soil.
    Degradation  of   2-nitroanlline   in   a   soil  mineral   salts   suspension
 occurred  in  >64 days, as  determined  by 100%  loss of UV absorbance (Alexander
 and Lustigman, 1966).
 2.3.2.    Adsorption.   The  K    of  an  organic  compound  can  be  estimated
 from the  following regression-derived equations  (Lyman, 1982):
          Log KQC -- -0.55 log (water solubility in ppm) f 3.64
          Log KQC = 0.937 log KQW - 0.006
 Based  upon  a  water  solubility  of  1470  ppm and  a  log  K   of 1.85  (see
 Section 1.2.).  the  KQC  for  2-n1troan1l1ne  is  estimated at 53-79,  Indicat-
 ing high  soil mobility  {Swann  et  al.,  1983).   Although high soil  mobility Is
 predicted,   2-nitroanillne  undergoes  strong  covalent  binding   with   humlc
materials.   Aromatic amines  (such as  the chloro- and methylanlUnes) undergo
covalent  binding with humates  (Parris,  1980).  An  initial  rapid  (and revers-
 ible)  binding phase  is  followed by  a  slow  reaction  (that  is   not  readily
reversible),  in which  the amlne  compound  is chemically altered  to  yield an
amino-substltuted  quinone.   This  covalent   binding  process   represents  a
mechanism  In  which  aromatic amines may  be  converted to latent forms  in  the
biosphere (Parris,  1980).
0318d
-6-
01/17/90

-------
     If  2-nHroanl 1 Ine  undergoes  covalent  binding  1n  the terrestrial  environ-
 ment,  leaching  will  not  be  significant.   However,  In  the absence  of  covalent
 binding,  significant leaching may be possible,
 2.4.    SUMMARY
     When  released  to the atmosphere, 2-n1troan1l1ne will  degrade  rapidly  by
 reaction  with  photochemically   produced  hydroxyl  radicals.   The  estimated
 half-life  for  this  reaction  In  average  air  Is  -11  hours  (Atkinson,  1988).
 By  analogy to  the aromatic  amlne  chemical  class  (Parrls, 1980),  2-n1tro-
 anlUne may  undergo covalent binding to  humlc  materials  1n soil  and  water.
 This  covalent  binding process may  represent a mechanism by which  2-nltro-
 anlUne may  be  converted  to a  latent  form  In the  biosphere.   If  covalent
 binding does  not occur,  2-n1troan1l1ne may  leach  readily  in soil,  based  on
 estimated  KQC  values  of  53-79  (Lyman,   1982;  Swann  et  al.,  1983).  The
 results of various  biological  screening studies Indicate that  2-n1troan1l1ne
 either  resists  blodegradatlon or Is  only slowly  blodegraded (KHano,  1978;
 Urano and  Kato,  1986;  Young and  Affleck,   1974; PHter,  1976; Malaney,  1960;
 Hallas  and  Alexander,  1983;  Alexander   and  Lustlgman,  1966;   Zeyer  and
 Kearney,  1983).   Aquatic hydrolysis and  volatilization are not  significant
 fate processes.
0318d                               -7-                              05/21/90

-------
                                 3.   EXPOSURE

    The  National   Occupational  Exposure Survey  (NOES)  estimated  that  1611
U.S.  workers  are   potentially exposed  to  2-n1troan1line  (NIOSH,  1989).   The
NOES  estimate  1s based upon NIOSH surveys of U.S.  industry  conducted between
1981 and 1983.
    Occupational exposure  to  2-nltroan1l1ne is  possible  during  Its produc-
tion  and use  as a  chemical Intermediate.   The most  likely  route of exposure
In  occupational  settings  Is  by  dermal contact  (NCI,  1985).   Exposure  by
inhalation Is  probably low because  nltroanlHne  Is a solid at room tempera-
tures with a low vapor pressure  (NCI,  1985).
    2-NHroanlllne  can  be  produced  during  both the aerobic  and anaerobic
Incubation  of 1,2-dlnltrobenzene  in   sewage  (Hallas and  Alexander,  1983).
This  suggests  that   2-n1troan1l1ne  may  be present  in  some environmental
samples  as  a  result  of  dlnHrobenzene blodegradatlon,  rather  than  direct
anthropogenic release.
3.1.   HATER
    Published  monitoring  data pertaining  to the detection  of  2-nltroanlllne
1n  environmental waters  are very limited.  2-NHroan1l1ne  was qualitatively
detected 1n  the River Waal  at  Brakel  in  the  Netherlands  during monitoring
between  1972  and   1974 (Meiers  and  Van  Der  Leer, 1976).  A  2-nHroan1l1ne
concentration  of 1 ppb  was  detected  In the Rhine  River  at Loblth, Nether-
lands  In 3uly, 1979  (Zoeteman  et  al., 1980).  A  compilation of chemicals
Identified   in  municipal   landfill   leachates  reported   a   2-n1troan1l1ne
concentration of 180 mg/i (Brown and  Donnelly,  1988).
0318d                               -8-                              05/21/90

-------
     The  U.S.  EPA (1989) STORET Data  Base  contains  30 positive detections of
 2-nHroanlllne  1n surface waters.  The maximum,  minimum and mean concentra-
 tions  for these  positive  detections  reported  by STORE! are  1.70,  0.09 and
 0.55 pg/l, respectively.
     Chemical  Intermediates  used  in  the  synthesis  of dyes and pigments can be
 emitted  to  the  environment  In  wastewater  streams generated  at production
 sites  (Steadman  et al.,  1977).   Since  2-n1troan1line 1s widely  used In dye
 synthesis  (see  Section 1.4.), 1t may be  released to the environment through
 wastewater effluents.
 3.2.   FOOD
     Pertinent  monitoring  data  regarding  levels  of  2-n1troan1l1ne   1n  food
 were not  located  1n the available literature cited In Appendix A.
 3.3.   INHALATION
    Pertinent  monitoring  data  regarding  Inhalation  exposure   of  2-nHro-
 anlllne were not  located In the available literature cited In Appendix A.
 3.4.   DERMAL
    Pertinent  monitoring data  regarding  dermal  exposure of  2-n1troan1l1ne
 were not located  In the available literature cited In Appendix A.
 3.5.   SUMMARY
    The  National  Occupational  Exposure  Survey  (NOES)  estimated that  1611
 U.S.  workers  are  potentially  exposed  to  2-nltroanlllne   (NIOSH,  1989).
 Occupational  exposure  to  2-nltroanlllne  is possible  during  Its  production
 and  use  as a  chemical Intermediate.   The  most  likely route.of  exposure  In
 occupational settings  Is by dermal  contact.   Inhalation  exposure  Is  probably
 low  because  n1troan1l1ne Is  a  solid  at  room  temperatures  with  a low  vapor
 pressure   (NCI,   1985).    The  use   of   2-nHroan1l1ne  In   dye  synthesis
0318d                               -9-                              05/21/90

-------
suggests  that  it  may be released to  the  environment  in  wastewater  effluents
From dye  production  (Steadman  et al., 1977).  2-NHroaniline may also  occur
in  the environment  as  a microblal  decomposition product  of  dinitrobenzene
(Hallas  and Alexander,  1983).   Pertinent  monitoring  data regarding  food,
Inhalation  and  dermal  exposure  of  2-n1troanil1rie  were  not  located  in  the
available literature cited in Appendix A.
0318d
-10-
01/17/90

-------
                          4. ENVIRONMENTAL TOXICOLOGY
 4.1.   AQUATIC TOXICOLOGY
 4.1.1.   Acute   Toxic   Effects   on  Fauna.    Pertinent  data  regarding  the
 effects  of  acute  exposure  of   saltwater  fauna  to  2-n1troan1l1ne  were not
 located  In  the  available  literature  cited  In  Appendix  A.   Studies  with
 freshwater  fauna Include  a  14-day study with the guppy, Poecllla retlculata.
 which  resulted  1n  an LC5Q  of   70.79  pmol/i  (9.8  rng/a)  (Deneer  et  al.,
 1987).   Loeb and Kelly (1963)  reported no  effect  1n  carp, Cyprlnus carplo.
 that were  force-fed  the test  article at 163, 177 and 189 mg/kg  for 22 hours.
 Applegate  et al. (1957) found no  effects  In larval  sea lampreys, Petromyzan
 marlnus, exposed to  5.0 mg/i for  24  hours.
 4.1.2.   Chronic Effects on Fauna.
    4.1.2.1.   TOXICITY — Pertinent  data  regarding  the effects  of  chronic
 exposure  of  aquatic   fauna  to   2-n1troan1l1ne  were   not   located  In  the
 available literature cited In Appendix A.
    4.1.2.2.   BIOACCUMULATION/BIOCONCENTRATION — Sasaki   (1978)   reported
 that  2-n1troan1l1ne   Is  nonaccumulatlve  or   Is  slightly  b1oaccumu1at1ve.
 Tests were  conducted with carp  exposed  to  the test article under flowthrough
 conditions  at  25DC  for ~8 weeks.  In evaluating  the results of bloaccumula-
 tlon  tests,  an  8-week  BCF  exceeding  "a  few hundred  times"  Is  typically
 considered  to be  highly  bloaccumulatlve,   whereas  criteria  for  judging  a
 chemical to  be of low bloaccumulatlon potential were not described.
 4.1.3.   Effects on Flora.
    4.1.3.1.   TOXICITY — Pertinent  data   regarding  the   toxic  effects  of
 exposure  of  aquatic  flora  to   2-nltroanlllne  were   not  located  In  the
 available literature cited 1n Appendix A.
0318d                               -11-                             05/21/90

-------
    4.1.3.2.   BIOCONCENTRATION — Pertinent  data  regarding  the  bloconcen-
 tratlon  potential  of  2-nitroan1l1ne  In  aquaUc  flora  were  not  located In the
 available literature cited In Appendix A.
 4.1.4.   Effects  on  Bacteria.  Ihe  effects  of  2-nltroanlUne  on growth  of
 the  dilate,  Tetrahymena  pyrlformls.  were  Investigated  by  Schultz  and
 Applehans (1985).   Cultures  of the  dilates  were  grown at  28°  under static
 conditions,   and  cultures were  tested with  50  ms. of  the  test  substance  at
 five  different concentrations.   The  60-hour  IGC5Q  was  115.55  mg/8, (0.837
mmol/l).
 4.2.   TERRESTRIAL TOXICOLOGY
 4.2.1.   Effects  on  Fauna.    Schafer  et  al.  (1983)  examined the  acute  oral
 toxldty  of  2-nltroanillne   to  birds.   The  LD  s  for redwing  blackbirds,
Aegelaius  phoenlceus.  starlings,  Sturn Is  vulgar Is.  the  Coturnlx  quail,
 Coturn1x  coturnlx,  and   the  house  sparrow,  Passer   domestlcus.  were  750,
>1000, 750 and 750 mg/kg, respectively.
4.2.2.   Effects   on   Flora.    Pertinent  data   regarding    the   effects   of
exposure  of  terrestrial  flora to  2-n1troan1lIne were not  located  in  the
available literature dted in Appendix A.
4.3.   FIELD STUDIES
    Pertinent  data  regarding the  effects  of  2-n1troan1line  on flora  and
 fauna  in the  field  were not  located  in  the available literature  dted  1n
Appendix A.
4.4.   AQUATIC RISK ASSESSMENT
    The  lack  of pertinent data regarding  the effects  of exposure of aquatic
fauna and flora to 2-n1troan1l1ne precluded the development of  a freshwater
criterion by  the  method   of U.S.  EPA/OWRS (1986).   Additional  data  required
for the  development  of a freshwater  criterion  include the  results  of acute
0318d
-12-
01/17/90

-------
assays with  a  salmonld  fish  species,  a  warm water fish species, a third fish
species  or  an amphibian,  planktonlc  and  benthlc  crustaceans,  an  Insect,  a
nonarthropod and  nonchordate  species  and an  Insect  or  species  from a phylum
not  previously  represented.   The development of  a  freshwater  criterion will
also  require data from chronic toxUHy tests with  two species of fauna and
one  species  of  alga  or  vascular  plant  and at  least  one  bloconcentratlon
study.
    The  lack of  pertinent data regarding  the effects  of  exposure of aquatic
fauna  and  flora  to  2-nltroanlllne  precluded  the  development of  a saltwater
criterion by  the method  of  U.S.  EPA/OWRS   (1986).   Additional  data  required
for  the  development of  a saltwater  criterion  Include the results  of  acute
assays with  two  chordate species  a nonarthropod  and  nonchordate  species, .a
mysld  or panaeld crustacean,  two additional  nonchordate  species  and  one
other  species  of  marine  fauna.   The development of  a  saltwater  criterion
also  requires data  from chronic  toxlclty tests with  two species of fauna and
one  species  of  algae  or  vascular  plant  and at  least  one  bloconcentratlon
study.
4.5.   SUMMARY
    The  lack of  adequate  freshwater and  saltwater  toxlclty and  bloconcentra-
tlon  data  with both  flora  and fauna  precludes  the development  of  criteria
for 2-nltroanlllne.  The  larval sea lamprey was not  affected  when exposed at
5.0  mg/a. for  24  hours  (Applegate  et a!.,  1957);   9.8  mg/s,  was  the  14-day
1C    for  gupples  (Deneer  et  al.,  1987).   Carp  that were force-fed  2-nltro-
anlllne  at a dose <189 mg/kg suffered no  observed adverse effects (Loeb and
Kelly, 1963).   The  dilate  bacteria,  Tetrahymena pyrlformls.  had a 60-hour
IGC5Q  of   115.55  mg/i  (Schultz  and  Applehans,   1985).    2-NHroanallne
0318d                               -13-                             05/21/90

-------
LDggS  for  the redwing  blackbird,  starling,  coturnlx and  house  sparrow were
750, >1000, 750 and 750 mg/kg, respectively (Schafer et al., 1983).
0318d
-14-
05/21/90

-------
                                        5.  PHARMACOKINETICS
            5.1.   ABSORPTION
A            Pertinent  data  regarding  the  absorption  of   2-nHroaniline  were  not
            located  In  the  available  literature  cited   In  Appendix  A.   However,  Its
            Isomer,  4-n1troan1l1ne,  Is  readily absorbed from the gastrointestinal tract,
            from  the peritoneal  cavity  and  through  skin (U.S.  EPA,  1985).   Since the two
            compounds  have similar  K  s  (Index  of hydrophoblclty}  and  pK  values  <1,
                                     OW                                    a
            It  Is likely  that  2-n1troan1l1ne   Is also  readily absorbed.   In an  English
            abstract  of  a Russian  study  of   permissible  concentrations   of  nltroamlno
            compounds  In  reservoir  waters, Mostcalenko  (1966)  reported  that all  three
            (presumably  orally  administered)  Isomers  of nltroanlllne  affected hematology
            parameters  1n  acute and  subacute protocols with guinea pigs,  rats  and  mice.
            Indicating  that absorption  from the gastrointestinal  tract  had occurred.   In
            a  similar   abstract,  Vasllenko  et  al.  (1974)  reported  "a  skln-resorptlve
            effect" for all three Isomers In rats.
            5.2.   DISTRIBUTION
               Pertinent  data   regarding   the  distribution  of  2-nltroanlllne  were  not
            located In the available literature cited In Appendix A.
            5.3.   METABOLISM
               Five hours after  IntraperHoneal  administration  of  2-n1troan1l1ne at  TOO
            nmol/kg  (13.8  mg/kg)   to  male   Wlstar   rats,   unspecified   d1azo-pos1tive
           metabolites were identified In  the urine (Watanabe  et al., 1976).
            5.4.   EXCRETION
               When Mate  et  al. (1967) treated  male  rats  IntraperHoneally with  10  mg
            [l4C]p-n1troan1line  per   animal,   76.5%  of  the dose  was  excreted  In  the
            urine within  24  hours.   If the o-lsomer  behaves similarly to  the  p-lsomer,
            It can  be  Inferred   that  a  large  fraction of  IntraperHoneally administered
           2-nltroanlllne or  Its metabolites  Is excreted  In the urine.

           0318d                               -15-                             05/21/90

-------
5.5.   SUMMARY
    Five hours  after  intraperHoneal  administration of  2-n1troan1l1ne at  100
>imol/kg  (13.8  mg/kg)   to   male   Wlstar   rats,   unspecified   dlazo-posltlve
metabolites were  Identified  In  the urine (Watanabe et  al., 1976).   Although
there are  few data  relevant  to  the absorption  of  2-nHroan1Hne (Moskalenko,
1966; Vasllenko et  al.,  1974),  the similarity of  Us  properties  to  those of
the  4-1somer,   which   Is  known  to  be  rapidly  absorbed  when  administered
orally,  IntraperHoneal ly  or  dermally  (U.S.  EPA,   1985),   suggests   that
2-nltroanlltne may  also  be  readily absorbed when given by  these  routes.   If
the o-isomer behaves similarly  to  the  p-lsomer, a  substantial  fraction  of an
1ntraper1toneally administered  dose of  2-n1troan1l1ne  or  Its  metabolites  may
be excreted 1n the urine  (Mate et  al., 1967).
0318d
-16-
02/15/91

-------
                                             6.   EFFECTS
           6.1.   SYSTEMIC TOXICITY
           6.1.1.   Inhalation Exposure.
               6.1.1.1.   SUBCHRONIC —According  to  Bio/Dynamics  (1983a),  aerosols  of
           0  (vehicle)  10,  28 or  73  mg/m3  2-nltroanlllne  In cellosolve  vehicle were
           given  to groups  of 10 Sprague-Dawley rats  per  sex,  6  hours/day, 5 days/week
           for 4  weeks  In Inhalation chambers.  The  concentration  of  cellosolve In the
           air  was  -2000  mg/m3   \n  all  groups.    Particle  size  was  determined  for
           samples  taken   from four  to  six of  the  exposures,  and  the   count  median
           diameter  was  0.5-0.9   vm   with   standard  deviations   of   1.1-2.2  and  no
           concentration-related  trend.  There was  no  treatment-related  mortality.   All
           exposed  groups had yellow  fur.   The 28  and 73  mg/m3 groups  had  Increased
           Incidence  of   dried red  nasal  discharge;  lacrlmatlon  was  reported  for  the
           latter  group.    There   was   no effect  on   body  weight  or  ophthalmoscoplc
           findings.   At  73  mg/m3, males  showed  a  significant  dose-related  decrease
^         In  leukocyte count,  and females  showed decreased  erythrocyte and hemoglobin
           values.  Both  sexes  of  this  dose  group  showed  variations  In  erythrocyte
           morphology, Including  polychromla, anlsocytosls and polkllocytosls.   Methe-
           moglobln values  showed  slight, but  not significant,  Increases at  the  high
           dose.   Serum calcium concentration Increased significantly  above concurrent,
           but  not historical,   controls In  mid- and  high-dose  males.    Microscopic
           examination  of  a  wide   range of   tissues  from  rats   In  the  control  and
           high-dose  groups,  Including   the  eyes   and  nasal   turblnates,  revealed  no
           compound-related  adverse effects,   except  on  the  testes.   The  testes  of
           high-dose males had lower absolute and  relative weights  with  degeneration  of
           germinal  epHhella.   The  testes  of  rats  In  the  other  exposed  groups
           exhibited no  effects   of  treatment.   High-dose  females  had higher  relative
           liver  weights   (B1o/0ynam1cs,  1983a).

           0318d                                -17-                             05/21/90

-------
     Subsequently,  Monsanto  (1983) reported  finding  new data 1n  the  litera-
 ture  on  effects   of  cellosolve  on   the  reproductive  system;  therefore,  a
 second  study  was  performed.   Ten  male Sprague-Dawley rats/group were  exposed
 In  chambers  to  vapor/aerosols  of  0,  9.8  and  93  mg/m3   2-n1troan1l1ne  6
 hours/day,  5  days/week  for  4 weeks   (B1o/Dynam1cs,  1983b).   The  atmospheres
 were generated  by passing warmed  nitrogen over heated  2-n1troan1l1ne In the
 absence  of  cellosolve  at  controlled  rates.    Controls were  subjected  to
 atmospheres containing  warmed nitrogen without passage over 2-n1troan1l1ne.
 The mean  count  median  diameters for   the  particles  In the air In  the  control
 and  low-dose  groups were 0.53 and 0.55  ym  with  standard deviations  of 1.9
 and  2.1,   respectively,   In  chambers   maintained  at  26°C.    Monsanto  (1983}
 Interpreted  the  similarity  In particle  size  1n  the  control  and  low-dose
 chambers  to suggest  that virtually  all  the  2-nltroanlllne present   In the
 low-dose  chamber  existed as  a vapor.   In  the high-dose group,  the  average
mass median diameter  and standard deviation  were  reported as 3.5  and 2.7
 iim,  respectively.  No  mortalities were  reported.   The exposed groups had
 yellow  fur  and  secretory responses such  as  Iacr1mat1on, mucold or  dried red
 nasal discharge,  especially  1n  the  later  weeks.    In  the   high-dose  group,
methemoglobtn and hematocrlt  were Increased and leukocyte  counts (segmented
 neutrophlls) were decreased  relative   to  concurrent  controls.  Only methemo-
globln  was  outside the range of historical  controls.   There were no  effects
 on  body weight,  organ  weights or the  gross appearance of  a  wide range of
 tissues,  Including the  testes.    Hlstopathologlcal  examination,  limited to
 the testes and epldldymus, revealed no compound-related changes.
    Vasllenko et  al.   (1974)  reported that hemotoxlc effects of  2-n1troan1-
 llne were  less  pronounced than were  the decreases  In  hemoglobin concentra-
 tion and  erythrocyte  count   In  rats   exposed  to  5  mg/m3 4-n1troan1l1ne,  5
hours/day for 4 months.
0318d
-18-
05/21/90

-------
     6.1.1.2.    CHRONIC  —  Pertinent  data  regarding the  systemic  toxlclty of
 chronic   Inhalation  exposure  to  2-n1troan1l1ne  were  not  located   In  the
 available  literature cited  In Appendix A.
 6.1.2.   Oral Exposure.
     6.1.2.1.    SUBCHRONIC  — Moskalenko    (1966)    reported    that   subacute
 (presumably  oral)  Intoxication  of  mice  and  guinea  pigs with 2-n1troan1lIne
 was  associated  with  Increased  hemoglobin,   erythrocytes  and retlculocytes,
 along  with the  presence of Heinz bodies,  and that these effects were accen-
 tuated  relative to acute  Intoxication.   Dose and  duration  of exposure were
 not  reported.   Vasllenko et al. (1972} reported  that  oral  administration of
 2-n1troan1l1ne  to  rats  at 0.1-0.2  LD     for  30  days  caused transformation
 of  hemoglobin  to methemoglobln, nltrosylhemoglobin  and sulfhemoglobln.  The
 Increased  levels of methemoglobln  and  sulfhemoglobln were  associated with
 decreased  oxyhemoglobln, but total hemoglobin was unaffected.
     6.1.2.2.   CHRONIC  — Pertinent  data  regarding the  systemic  toxldty of
 chronic  oral  exposure   to  2-n1troan1l1ne  were  not  located  In  the  available
 literature cited In Appendix A.
 6.1.3.   Other   Relevant  Information.   Younger  Laboratories  (1977)  found
 transient  Irritation   to the  eyes   and  no   Irritation  to   the  skin   of  New
 Zealand  white   rabbits  from  topical  applications  of  50 and 500 mg  finely
 ground  2-nltroanlline  moistened with  water  to the eyes  and  skin,  respec-
 tively.   Oral   and  dermal  LD.._ values  are  summarized 1n  Table 6-1.   The
                              DU
 oral  L05  for  rats  were 535-3520  mg/kg.   The limited  data  do  not  suggest
major differences  In the acute toxldty of  2-nltroanlllne  to rats, mice and
guinea pigs.
0318d                               -19-                             05/21/90

-------
                                  TABLE  6-1

                        LD50 Values for 2-NHroan1Hne
Species/Strain    Sex      Route of      L05p Value
                       Administration    (mg/kg)
                        Reference
Rats/
Sprague-Dawley
Rats/
Sprague-Dawley
Rats/NR
Rats/NR
Mice/NR
Guinea pigs/NR
M,F
M,F
NR
NR
NR
NR
dermal
oral
oral
oral
oral
oral
7940
2050
535
3520
1246.1
2350
Younger Laboratories,
1977
Younger Laboratories,
1977
loxlc Substances List,
1974; RTECS, 1975
Vasllenko et al.. 1974
Moskalenko, 1966
Moskalenko, 1966
NR = Not reported
0318d
-20-
01/17/90

-------
     Haskell  Laboratories  (1981)  exposed groups of  10  male  CM:CD rats (head
 only)  for  4  hours  to  1.1-12.02  mg/i  2-nltroan1lIne  aerosols/vapor  con-
 talning  mlcrocrystalllne  particles  with  MHAD  ranging  from  4-11   vm  and
 geometric   standard  deviations   ranging  from  1.16-1.84.    There  were  no
 mortalities  at  concentrations  <6.6  mg/i;  however,   at  concentrations  of
 7.55-11.66   mg/i,   1/10-6/10   rats  died  with   In   2-4  hours   of   Initial
 exposure.   This  effect  was   not  considered  dose-related.   Lack of  dose-
 related  mortality  precluded  determination  of  an  LC  ,  and  the approximate
 lethal  concentration was estimated  to be  >12 mg/a.   Clinical  signs,  other
 than  mortality, were  bright   orange  urine,  slight corneal  opacif1cat1on  24
 hours  after  exposure that cleared  in 2-3  days  and  2-5% weight  loss  In  the
 first  24  hours with  normal   gains  afterward.   Necropsies  showed  slightly
 enlarged livers and congested, mottled lungs.
    A  single Intraperltoneal  Injection  of  100 pmol/kg  (13.8  rug/kg) or  in
 vUro  Incubation   of  0.5  ymol  2-n1troanlline  with  0.1   v^ol  hemoglobin
 resulted  In  methemoglobln  formation  in  the blood of  male  rats  (Watanabe  et
 al.,  1976).  Hoskalenko  (1966) reported  that  acute (presumably oral)  Intoxi-
 cation of  mice and  guinea  pigs at  the  LD5Q  for  2-nltroanlllne  resulted  In
 spasms and  Increased hemoglobin, erythrocytes  and  retlculocytes,  along  with
 Heinz  bodies,  leukocytosls,  neutrophils  and   lymphopenla.  Vasllenko  et  al.
 (1974)  reported  that  2-n1troan1lIne  showed   hepatotroplc  properties  when
 orally  administered  to   rats   at   half   the   L0|-n-    Kolodub  and  Vasllenko
 (1976)  reported  that  20%  of   the  oral  LD5Q  for  2-nltroanlllne  inhibited
 electron transfer and decreased ATP synthesis  In livers of rats.
 6.2.   CARCINOGENICITY
 6.2.1.   Inhalation.   Pertinent   data   regarding  the   carcinogenicity   of
 inhaled  2-n1troan1l1ne  were  not located  in the available  literature  dted
 1n Appendix A.

0318d                               -21-                             05/21/90

-------
6.2.2.   Oral.   Pertinent  data  regarding  the  carclnogenlcity   of   orally
administered  2-nHroannine were  not  located  In  the  available  literature
cited In Appendix A.
6.2.3.   Other Relevant  Information.   Pertinent  data  regarding the carclno-
genlcHy of  2-n1troan1l1ne  administered  by other routes were  not  located  1n
the available literature cHed In Appendix A.
6.3.   GENOTQXICITY
    Relevant  genotoxldty  data  for  2-nHroan1l1ne  are  presented \r\  Table
6-2.  The  data  are mainly negative.   In  prokaryotes,  2-n1troan1l1ne  Induced
reverse  mutations  In  tester  strains  1A98  and  1A1598  of Salmonella  typjij-
murlain,  both of  which  are  sensitive  to  frameshift  mutations,  but  not  In
strains  TA100 or  TA1535,  both  of which are  sensitive  to  base-pair substitu-
tions  (Garner  and Nutman,  1977;  Chlu et  al.,  1978;  Thompson et  a!.,  1983;
Shlmizu  and  Takemura,  1983;  Le et  al.,  1985; Shlmizu and  Yano, 1986).   A
recent publication  confirmed  the  low mutagenic potential of  2-n1troan1l1ne
1n  Salmonella  ty^hjmurium  (strains  TA98  and TA100)  {Dellarco and  Prival,
1989).   This  study  was done under  conditions allowing for  the  reduction  of
the nitro  group.   Revertants  were not Induced  In Escherlchla  coll (Thompson
et al.,  1983),  but  2-nitroaniline was positive  In  the  differential  toxidty
test  in  Bacillus  subtllis  (Shimizu  and  Yano, 1986).   In mammalian  systems,
results  were  entirely negative.   Iji  vitro.  2-nltroaniline  failed to  Induce
unscheduled DNA repair  1n rat hepatocytes  (Yoshimi  et  al.,  1988;  Thompson  et
al.,  1983);   in  y_1_y_o.   It  failed  to  Induce  strand  breaks  detectable  by
alkaline elution in Swiss mice (Cesarone et al., 1982).
6.4.   DEVELOPMENTAL TOXICITY
    In a range-finding  study, groups of six  mated  Crl:CO  rats were  given  0,
50,  200,  400,  800  or  1200  mg/kg  2-n1troan1l1ne  in  corn oil by gavage  on
0318d
-22-
02/15/91

-------












Genotoxlclt













0>
c
4)
OS


•£

LJ


C
0
f^
I/I
ID
ac.
*•• ti
u
B
0
—• tl
rQ wl
1. 0
*-> 0
e
CU L.
u O
c
0
~ £.
a.
c
o
~
2
Q.

E
VI
C
Ol
o
o
ID
•o
c

4/1
<

"2 ^ •" o^ l= jS " c*o cncsD ;r» sr»
|| Is 1- ll ^g ll f^ |=" 1^-5'
• C
OC 4; o O i— O OC ^rftf_
C3 "O 4* L_ ^_ c • w C!) "O •*— cn
•"* *t3 > 4J O i*" O *— ty f £
3^* ^^13!£?>» i-oS^— i
OC CO U *-• QJ OC C*-i
**-O er»E3^E^ *-o — o
— < O -o E O c *- c
i ' I- C 3
Oj C CO tO O 0> t/) v^ 0*CW !
•^ (U Z ^ W C ^ U U *
O t_) OkO U C-^^C-^StJ O.O ^*rf t_) <_>
Z Z  *3 2«; . '.T, "3 2o-
it-t3> i "O > I •^ > t 'Q >
«
;*• i— Q. ot 'cr ti
4)0 X 6 0 1) -x. OOO
O **-iO D* O^'O) O«<^M|MM
o <— 10 o a. LT> o ID E OE
•f *&'E O p«-*« '& u"t i »™" n IA
o-™" -an-cft oe vn ••— >o> - -Eoo
00
ac aeoc CKCT o^oeo> CKCX:
Z Z Z Z Al CTi Z Cn ZZ
c c c c c c
ooo o oo I; 41
U ISIS SIS «B 'Sg «< 5 —
„! o-l .1 2! «l .1 «l ^ 33
^-C •— C •— C —3^-C •— C F— C Q. 0) U
m
E * i oi
.^ ^ »— t— i— T- J^maaEvi'Q
^: «. — — 0.0. o *• a.
a EEl— oo E E E- o — u i_ u>aai
2 lsll*llsl 15 i, ^iii. t," 1
00 h- (/>lh- (/>!(— ^- O CAlt— W>l>— C/>l^ h- u^3 CO Z X at fU. 1-
•si -I
C C C CC CC<« 3 *» 3-^
HO UOOIO IP O Q) O «J O It O O. -0 C T3 C
4><9 ajroai'Q aji^tt'o aifQ AITI u w
0) 3 0130)3 0130)3 0)3 0)3 Z C Z C Z
at e oeEaeE ce E QC e oe S aeE o 30=0
0318d
-23-
08/16/90

-------
         I     —
    01

   Uw

    (U

   at
            — COCO

            U «- T3 3 *-
   IP
   ae
   •" 4)

   <» VI

   l_ O
   0> k-
   u O
            01 — V
            ct>— •>-•
            ig ig U
            i- Ol »>
            ~* c —^
            c o c
            S

            01
            z m i—
            O ••— 4)
                            O
                            C


                            II
                            o
                            o.
                            Ol
0318d
-24-
08/16/90

-------
gestation  days  6-15  (Monsanto,  1984).   Four  dams  died  In  the  highest dose
group;  mean  maternal  body weight gains and  food  consumption were reduced In
the  two highest  dose  groups.   Clinical signs  exhibited by dams  In  the two
highest  groups  Included  hypoactlvlty,  convulsions,  salivation,  prostration,
piloerectlon,  shallow  respiration  and loss  of  muscle  coordination.   All
treated  dams had yellow  stains  on their  fur.   No  effects were  seen  on the
mean  number  of  viable  fetuses,  total  Implantations  or  resorptlons.   Mean
fetal body weights  were  depressed  only  at  the two higher doses.   No external
malformations were  found  (Monsanto, 1984).
    Based  on the  Monsanto (1984)  range-finding  study,  groups  of 25  mated
Charles  River  CD  rats  were  given  0,  100,  300  and  600  mg/kg/day  2-nltro-
anlUne  In  corn  oil  by  gavage  on  gestation days  6-15  (Monsanto,  1985).
There were no  treatment-related  mortalities  In the  dams.  Transient  maternal
toxldty  In  the 300 and  600  mg/kg/day groups was  Indicated by  plloerectlon
and pale  or  cold extremities.   Maternal  weight gains were  depressed  In the
600  mg/kg/day  group.    Food  consumption  was  reduced   In  the  300  and  600
mg/kg/day  groups,  especially  during   treatment.   There  were no  chemical-
related  effects  on  pregnancy  rates,  fetal  resorptlons,   fetal  viability,
postlmplantatlon  losses,   total  Implantations  or mean  litter weights.   One
fetus In each of two Utters of high-dose dams had situs Inversus syndrome.
6.5.   OTHER REPRODUCTIVE EFFECTS
    Pertinent  data  regarding  other reproductive  effects  of  2-n1troan1l1ne
were not  located  1n the  available  literature dted In  Appendix  A.   Recall,
however,  the Bio/Dynamics  study  (1983a)  referred  to  In  Section  6.1.1.1.
where absolute and  relative testlcular  weight  was  reduced In rats exposed to
73 mg/m3 2-n1troan1l1ne In cellosolve vehicle.
0318d                               -25-                             02/15/91

-------
 6.6.    SUMMARY
    Two  studies  by Bio/Dynamics reported  effects  In  rats that were  exposed
 by  Inhalation  to  vapor/aerosols of  2-n1troan1l1ne 6 hours/day,  5  days/week
 for 4  weeks.   In  the  first  (B1o/Dynam1cst 1983a), 2-nltroan1l1ne  at  0,  10,
 28  or  73 mg/m3  mixed  with  2000 mg/m3 cellosolve  was  given to  both  sexes;
 In  the  second study  (Bio/Dynamics,  1983b),  rats  were  exposed to 0,  9.8 or 93
mg/m3  In the  absence  of cellosolve.   Secretory  effects   (nasal  discharge
and lacrlmatlon)  were  reported In  the first  study at  >28  mg/m3 and  In  the
second  study  at  9.8  mg/m3.   At   73 or  93  mg/m3,  males  had  decreased
 leukocyte  counts.   Females   showed  decreased  erythrocyte  and  hemoglobin
values  and  higher  relative  liver  weights  at 73  mg/m3.   Both  sexes  showed
altered  erythrocyte  morphology and  slight,  but  not significantly elevated
methemoglobln  levels   at   73  mg/m3.    At  93   mg/m3,  methemoglobln   and
hematocrit Increased  significantly.   Vasllenko et  al.  (1974)  reported hemo-
toxlc   effects  from 5  mg/m3  2-n1troan1l1ne given  5 hours/day  for  4  months,
but experimental  details were  lacking.   Moskalenko (1966)   and  Vasllenko et
al.  (1972)  also  reported  Increased  hemotoxlc  effects  from  subacute  oral
Intoxication.   Pertinent  data  regarding  chronic  exposure  to  2-n1troan1l1ne
by any route were not located.
    Acute  1ntraper1toneal  or  oral   administration of  2-nltroanlllne  caused
hemotoxlc effects  (Watanabe  et al., 1976;  Moskalenko,  1966).   Other  effects
of  acute  oral   administration were  spasms,  enlarged   livers  and  altered
oxldatlve phosphorylatlon  (Moskalenko,  1966;  Vasllenko  et al.,  1974;  Kolodub
and Vasllenko, 1976).  Topically applied as a paste 1n  water,  2-n1troan1l1ne
was transiently  Irritating to  the  skin and eyes  of rabbits  (Younger  Labora-
tories,  1977).   Acute  Inhalation  exposure to  7.5-11.7  mg/i  2-nltroanlHne
aerosol/vapor  for  4 hours   led to  mortalities  In rats,  with  no consistent


0318d                                -26-                             02/15/91

-------
            dose-response  trend  (Haskell  Laboratories,   1981).   The  oral   LDrQ  values
A         for  rats, mice  and  guinea pigs  were 535-3520 mg/kg  (Younger Laboratories,
            1977;  Toxic  Substances  List,  1974;  RTECS,  1975;  Vasllenko  et  al.t  1974;
            Moskalenko,  1966).   The  dermal  LD5   for  rats   was   7940   mg/kg  (Younger
            Laboratories,  1977).
                Pertinent  data regarding the  carcinogeniclty  of 2-nltroanillne adminis-
            tered  orally  or  by Inhalation or  other  routes of  exposure were not located.
            The  compound  was predominantly  nonmutagenlc (see  Section 6.3.).   In develop-
            mental  toxldty  studies, 2-n1troan1l1ne  caused maternal toxlclty (plloerec-
            tlon,  pale  or  cold extremities, depressed  weight  gain  and food consumption,
            hypoactlvlty,  convulsions,   salivation,  prostration,   shallow  respiration,
            loss  of  muscle  coordination  or  mortalities)  when  mated  rats  were given  800
            or 1200  mg/kg  by gavage  on gestation  days 6-15 (Monsanto, 1984; 1985).   Mean
            fetal  body  weights were  depressed at 800 and  1200 mg/kg.  One fetus in each
^.         of 2  of  25  litters of dams dosed with 600 mg/kg had situs Inversus syndrome.
            No  fetal effects  were  reported at dose  levels below  those  associated with
            maternal  toxlclty.
           0318d                               -27-                             02/15/91

-------
                     7.  EXISTING GUIDELINES AND STANDARDS
 7.1.   HUMAN
    Pertinent  guidelines  and  standards  for  2-n1troan1l1nef  Including  EPA
 ambient  water and  air quality  criteria,  drinking water  standards,  FAO/HHO
 ADIs,  EPA or  FDA  tolerances for  raw agricultural commodities  or  foods  and
 ACGIH, N10SH  or  OSHA  occupational  exposure limits, were  not  located  In  the
 available literature cited In Appendix A.
 7.2.   AQUATIC
    Guidelines  and  standards   for   the  protection  of  aquatic  life  from
 exposure  to  2-nHroan1l1ne  were  not  located  In  the available  "literature
 cited 1n Appendix A.
0318d
-28-
08/16/90

-------
                              8.   RISK ASSESSMENT
8.1.   CARCINOGENICITY
8.1.1.   Inhalation.    Pertinent   data  regarding  the   cardnogenldty   of
Inhaled  2-n1troan1llne  to  humans  or  to  animals  were   not  located  1n  the
available literature dted In Appendix A.
8.1.2.   Oral.   Pertinent  data  regarding  the  carclnogenldty  of  orally
administered  2-n1troan1l1ne  to  humans or to animals were not  located  In  the
available literature cited In Appendix A.
8.1.3.   Other  Routes.   Pertinent  data  regarding  the  carclnogenldty   of
2-n1troan1l1ne administered by other  routes  to  humans  or  to animals  were  not
located In the available literature cited 1n Appendix A.
8.1.4.   Weight  of  the  Evidence.    Because  there  are   no data  available
regarding  carclnogenldty of  2-n1troan1l1ne to  humans  or to  animals,  this
chemical 1s  placed In  EPA we1ght-of-ev1dence Group D  --  Not  Classifiable as
to  Human  Carclnogenldty, according  to guidelines  established by  the  U.S.
EPA (1986b).
8.1.5.   Quantitative  Risk Estimates.  Because 2-n1troan1l1ne  Is  classified
In  EPA we1ght-of-ev1dence Group  D and  quantitative  dose-response  data  are
not available, quantitative risk assessment cannot be performed.
8.2.   SYSTEMIC TOXICITY
8.2.1.   Inhalation Exposure.
    8.2.1.1.   LESS  THAN  LIFETIME  (SUBCHRONIC)  — Two   unpublished  studies
reported effects In rats  exposed  In Inhalation  chambers  to vapor/aerosols of
2-n1troan1l1ne  6  hours/day,  5  days/week  for   4  weeks.    In  the   first
(Bio/Dynamics,  1983a),  2-n1troan1l1ne  at  0,  10,  28 or  73 mg/m3 was  mixed
with  2000  mg/m3 cellosolve  and  administered  to  both  sexes.    In  the  second
study  (81o/Dynam1cs, 1983b),  only males were  exposed  to 0, 9.8 or  93 mg/m3


0318d                               -29-                             08/16/90

-------
 1n  the absence  of  cellosolve.   Signs of  local  Irritation  (nasal  discharge
 and  lacrlmatlon) were  reported  In the  first  study at  >28 mg/m3  (Rec.  #4,
 Appendix  C.2.1.) and  In  the second study  at  >9.8 mg/m3  (Rec.  #1,  Appendix
 C.2.1.).   Rats  In the  control and high-dose groups 1n  the  first  study  were
 subjected  to  a  comprehensive hlstopathologlcal  examination that  Included the
 eyes and  nasal   turblnates.  There  were  no  treatment-related hlstopathologl-
 cal alterations  1n  the eyes or nasal epithelium.   The  lacMmatlon and nasal
 discharges are  considered to be  the  result of  local  Irritation,  since  they
were not accompanied by evidence of hlstopathologlcal damage.
    In  the first study at  73  mg/m3 {Rec.  #3,  Appendix C.2.1.), and  1n  the
 second  at  93 mg/m3  (Rec.  #2, Appendix  C.2.1.), males  had  decreased  leuko-
cyte counts.  Females  showed decreased erythrocyte and  hemoglobin  values  and
higher  relative  liver weights  at  73  mg/m3.   Both   sexes  showed  altered
erythrocyte morphology and slight,  but  not significantly  elevated  methemo-
globln  levels  at  73  mg/m3.   At 93  mg/m3  {Rec.  #2,  Appendix  C.2.1.),
methemoglobln  and  hematocrlt  were  Increased  significantly.    These  data
 Indicate  that  the critical  effect of  Inhalation  exposure  to  2-n1troan1l1ne
 Is altered hematology.  Including  decreased  leukocyte count,  altered erythro-
cyte morphology,  hematocrlt  and  blood hemoglobin  concentration  and  methemo-
globlnemla  {B1o/Dynam1cs,   1983a,b).    Vasllenko   et   al.   (1974)  reported
hemotoxlc  effects  1n  rats  at  5 mg/m3  2-n1troan1l1ne  given 5 hours/day  for
4 months,  but experimental  details were lacking;  therefore,  this  study  Is
not considered adequate for quantitative  risk assessment.
    In  the first study (Bio/Dynamics,  1983a),  Intermittent exposure to  28
mg/m3  was  a  LOAEL for  nasal  and  eye Irritation (Rec.  #4,  Appendix C.2.1.),
and  Intermittent  exposure  to  73 mg/m3  was   a  LOAEL (Rec.  #3,  Appendix
C.2.1.)  for  hemotoxlclty.  Intermittent  exposure  to 9.8  mg/m3  was a  NOAEL
0318d
-30-
08/16/90

-------
           (Rec.  #1,  Appendix  C.2.1.)  and  Intermittent  exposure  to 93  mg/m3  was  a
           LOAEL  (Rec.  #2,  Appendix  C.2.1.)  for  hemotoxlclty  (B1o/Dynamics,  1983b).
           Since  9.8 mg/m3  did produce  Irritant effects  In the  Bio/Dynamics  (1983b)
           study  (Rec.  #1,  Appendix  C.2.I.),  however,  1t   Is  considered  a  LOAEL  for
           Inhalation exposure  to 2-n1troanalIne.
              As  Indicated  by Bio/Dynamics  (1983b) and Monsanto (1983),  particle size
           1n  the  control  and  low-dose groups was virtually  Identical.  Monsanto  (1983)
           Interpreted  this  observation  to  Indicate  that  virtually all  the 2-n1tro-
           anlllne present 1n  the air  at  the low dose was  present In the vapor form.   A
           LOAELHEC  can be  estimated  from  the  LOAEL  of  9.8  mg/m3  (Rec.  #1, Appendix
           C.2.1.)  In  the  Bio/Dynamics (1983b) study.  The  Intermittent  exposure  level
           of  9.8  mg/m3  1s  multiplied by  6 hours  of  exposure  per  24-hour   day  and  5
           days  of  exposure  per 7-day  week  to  estimate  an  adjusted equivalent con-
           tinuous  exposure  concentration  of  1.8  mg/m3.    The  adjusted  concentration
           of  1.8  mg  2-nltroanlllne/m3,   therefore,   1s  the  LOAELucr  {B1o/Dynam1cs,
                                                                     Mt L
           1983b).
              An  adjusted equivalent  continuous  exposure  concentration  of   5.0  mg/m3
           Is  estimated  by multiplying the 28 mg/m3  Intermittent  exposure level by  6
           hours of exposure per 24-hour day and by 5 days  of exposure per 7-day week.
              An RfC  for  subchronlc  Inhalation  exposure  can be estimated by applying
           an  uncertainty  factor  of  1000  (10  to  reflect  the uncertainties  In  the
          methodology  for estimating a HEC  from animal  exposure  data,  10 to  provide
          additional protection for unusually  sensitive Individuals,  and 10 for use  of
          a LOAEL  for  RfD  derivation)  to  the  LOAELUC_   of  1.8 mg/m3.  The  resulting
                                                     net
          RfC  for  subchronlc   Inhalation  exposure of  0.002 mg/m3  1s recommended  for
          exposure to vapors of 2-n1troan1l1ne.

O
          0318d                                -31-                              03/11/91

-------
    Confidence  In the  study,  based  on  observations restricted  to 10  male
animals  per  exposure   level  and   a  4-week   exposure   duration,   1s   low.
Confidence  1n  the data  base Is  low because the Bio/Dynamics  (1983a)  study
supports the NOAEL  In the key study,  because  other  data support hematologlc
toxUHy as  the  critical effect, and  because a  developmental  toxldty  study
did not  report  fetal  effects at  levels  below  those  associated with maternal
toxlclty.  Confidence In the RfC, therefore, 1s medium.
    8.2.1.2.   CHRONIC — Pertinent  data  regarding  the  systemic  toxlclty  of
chronic  Inhalation  exposure  to  2-n1troan1"!1ne were   not  located  In  the
available  literature  cited  In Appendix  A.   A  chronic Inhalation RfC may  be
calculated  by   dividing   the  subchronlc  RfC  by an  additional  uncertainty
factor of 10, giving a value of 0.0002 mg/m3.
8.2.2.   Oral Exposure.
    8.2.2.1.   LESS   THAN   LIFETIME   (SUBCHRONIC) ~ Abstracts   of   Russian
studies were not  compiled Into data records  In  Appendix  C.2.2., because data
that  associated  hemotoxlc   effects  with   subacute  oral  Intoxication  with
2-nltroanllIne  were   Inadequately  reported  (Moskalenko,  1966;  Vasllenko  et
a!., 1972).  Watanabe et al.  (1976) showed that  IntraperHoneal Injection  of
rats with 2-n1troan1l1ne also resulted In hemotoxlclty.
    In   developmental   toxlclty   studies,   2-n1troan1l1ne   caused   maternal
toxlclty  (Recs.  #1,   2,  4,  5, Appendix  C.2.2.)  when mated  rats were  given
300-1200 mg/kg/day by  gavage on  gestation days  6-15  (Monsanto,  1984;  1985).
Mean fetal  body  weights  were depressed at 800 and  1200  mg/kg/day (Recs. #1,
2, Appendix C.2.2.).   One  fetus  In each of  2 of 25  Utters  of dams  dosed  at
600 mg/kg/day  had situs  Inversus   syndrome  (Rec.  #4,  Appendix  C.2.2.).   No
fetal   or  reproductive effects were reported at  dose  levels  not  associated
with maternal toxlclty  (Recs.  #3,  5,  6, Appendix C.2.2.).   Since studies  of
0318d
-32-
03/11/91

-------
 oral  exposures of  sufficient detail  and  duration are  lacking,  an  RfO  for
 subchronlc  oral  exposure  to  2-nltroanlllne  cannot  be  derived  from route-
 specific  data.   Data regarding  other  nltroanlUnes administered  orally were
 also  Insufficient (U.S.  EPA,  1985),  precluding adoption of an RfD  for oral
 exposure  to  2-nHroanlllne  by  analogy  to   other   nltroanlllnes.   In  the
 absence  of  adequate  route-specific   data,  It  1s appropriate   to  consider
 deriving an  RfD for  oral  exposure from Inhalation  data.   As Indicated above,
 hemotoxldty appears  to be  the critical  effect of  exposure  to  2-nltroanlllne
 by any route of exposure.
    Since  the  local  Irritant  effects  seen   with   Inhalation  exposure  to
 2-nltroanaline  would not be  expected with oral  exposure,  the NOAEL of  9.8
 mg/m3  for  hemotoxldty in  the B1o/Dynamics  (1983b)  4-week  Inhalation  study
 can  also serve as  the  basis  for  a  provisional   subchronlc  oral  RfD.   As
 described   in   Section  8.2.1.1.,   the   9.8   mg/m3   Intermittent   exposure
 concentration  can be expanded  to an equivalent continuous  exposure  concen-
 tration  of  1.8  mg/m3.   In   the  absence   of   pharmacoklnetlc  data.  It  1s
 appropriate  to  assume that  steady  state may  have been reached  during each
 exposure  Interval.   Since  experimental blood:a1r  partition  coefficients  for
 2-nltroanlllne  1n humans  and  animals  are  unavailable,  It  Is appropriate  to
 assume an equivalent  value  for both  species.   Multiplying  this  concentration
 by the  reference  Inhalation  rate for  rats  of  0.223  mVday  (U.S. EPA,  1980}
 and  dividing by  the TWA body weight for  rats In  this group of  0.350  kg
 results  in  an  estimated Inhaled  dose  of  1.15  mg/kg/day.   In the absence  of
 adequate pharmacoklnetU data,  it Is  appropriate to assume  absorption of  50%
 of an Inhaled dose and 100%  of an Ingested  dose.   An  equivalent oral  dose  of
 0.58 mg/kg/day  Is estimated  by multiplying the Inhaled  dose by the  ratio  of
 percent  Inhalation  to percent   gastrointestinal  absorption.    Applying  an


0318d                               -33-                              08/16/90

-------
uncertainty  factor  of  1000 (10 to extrapolate  from animals  to  humans,  10  to
provide  additional   protection  for  unusually  sensitive  humans,  and  10  to
reflect  the  uncertainties arising  from  lack of sufficient  reproductive  and
oral  exposure  data)  results  in  an  RfD  for  subchronic  oral  exposure  to
2-nitroaniline of 0.0006 mg/kg/day.
    Confidence  in  the  key study,  based  on observations  In  10  male  rats  per
exposure level and  a 4-week  duration  of  exposure,  is  low.  Confidence in the
data base  Is  low,  primarily  because of  the  lack  of  sufficient  oral  exposure
data.  Confidence in the RfO, therefore,  is low.
    8.2.2.2,   CHRONIC — Pertinent data  regarding  the systemic  toxicity  of
chronic  oral  exposure to  2-nltroanlline were  not  located  in  the available
literature   cited    in   Appendix   A.     Therefore   the   chronic  RfD   for
2-nitroanallne must  be  calculated  by dividing  the above  subchronic  oral  RfD
by  an  additional  uncertainty  factor  of  10  to  account  for  the  use of  a
short-term  study for  chronic  RfD  derivation,  giving  a  value  of  0.00006
mg/kg/day.
0318d
-34-
03/11/91

-------
                           9.   REPORTABLE  QUANTITIES
9.1.   BASED ON SYSTEMIC TOXICITY
    There  were no  chronic or  subchronlc  studies of  sufficient detail  and
duration  that  could be used to derive  an  RQ ranking for 2-n1troan1l1ne.  The
U.S. EPA  (1985) derived  an RQ  of  100 for  4-nHroan1l1ne based on an abstract
of  a 90-day  study by Houser et al.  (1983)  In  which  3 mg/kg/day administered
to  rats  by gavage  decreased  the  oxygen-carrying  capacity of  the  blood  and
caused  splenic  hlstopathology.   2-N1troan1l1ne  administration  by  several
routes  for  a  shorter  duration  also  has hemotoxlc effects,  Including  methe-
moglobln  formation,  which  could decrease  oxygen-carrying  capacity  (Bio/
Dynamics,  1983a,b;  Vasllenko  et al., 1972,  1974; Moskalenko,  1966;  Watanabe
et  al.,  1976),  suggesting that p- and  2-n1troan1l1ne  cause  similar  effects.
Therefore,  the RQ  of  100 for the  4-1somer  Is  adopted  for  2-n1troan1l1ne
(Table 9-1).
9.2.   BASED ON CARCINOGENICITY
    Pertinent data  regarding  the  carclnogenldty  of  2-nltroanlllne  to  humans
or  animals  by  any  route  were  not located in  the available  literature cited
1n  Appendix A.   Therefore,  this  chemical   was  placed  In  EPA  we1ght-of-
evldence  Group D  (U.S.  EPA,  1986b)  --  Not Classifiable  as to Human Carclno-
genldty.   No  hazard  ranking  Is  possible  for  substances  1n  Group  D,  and
therefore, a carcinogenlcity-based RQ cannot  be derived.
0318d                               -35-                             08/16/90

-------
                                   TABLE 9-1
                                2-N1troan1l1ne
           Minimum Effective  Dose  (MED) and  Reportable Quantity  (RQ)
Route:
Species/Sex:
Dose3:
Duration:
Effect:
RVd:
RVe:
CS:
RQb:
Reference:
oral
rats/NR
4.7 mg/day
90 days
reduced oxygen-carrying capacity of blood
4.7
7
32.9
100
Houser et al.,  1983
Equivalent human dose
bThe RQ for 4-n1troan1l1ne was adopted for 2-nHroan1l1ne by analogy.
NR = Not reported
0318d
            -36-
08/16/90

-------
                                10.  REFERENCES

Alexander,  M.  and  8.K.  Lustlgman.  1966.   Effect  of chemical  structure  on
mlcroblal  degradation of  substituted  benzenes.   J.  Agrlc. Food  Chem.   14:
410-413.

Applegate,  V.C.,   J.H.  Howell,  A.E.  Hall,  Jr.  and  M.A.  Smith.   1957.
Toxldty  of  4346  Chemicals   to  Larval  Lampreys  and  Fishes.   Spec.  Scl.
Rep.-Fish. No. 207.   F1sh Hlldl. Serv.  USDI, Washington, DC.  157 p.

Atkinson,  R.   1988.   Estimation  of gas-phase hydroxyl  radical  rate constants
for  organic chemicals.  Environ. Toxkol. Chem.  7: 435-542.

Bio/Dynamics.   1983a.   Project  No.  81-75-35.   (BD-81-322).    A  four  week
Inhalation  toxlclty  study of  0-n1troan1l1ne  In  the  rat.   Final  report.
Submitted  to Dr.  Rashml Nalr,  Monsanto  Co.,  July  15,  1983.   Revised November
23,  1983.  EPA 878214178.  Flche #0150206486.  p.  1A-50,  142-149, 210-216.

B1o/Dynam1cs.   1983b.   Project  No.  (BD-82-270).   A four  week  Inhalation
study  of  ortho-nltroanlUne  In male rats.   Final Report.  Submitted  to  Dr.
Rashml  Nalr,  Monsanto  Co.,  August  16,  1983.   EPA 878214178.   #QTS0206486.
p. 1A-17, 32-42, 46-48, 55-58, 62-67.

Brown,  K.W. and  K.C.  Donnelly.   1988.   An estimation  of  the risk  associated
with  the  organic  constituents  of  hazardous  and  municipal  waste  landfill
leachates.  Hazard. Haste.  Hazard.  Mat.   5:  1-30.
0318d                               -37-                             08/16/90

-------
Cesarone,  C.F.,  C.  Bolognesl and  L.  Santl.   198?.   Evaluation of damage  to
DNA  after  jjn  vivo  exposure   to  different  classes  of  chemicals.    Arch.
Toxlcol.  5: 355-359.

Chemllne.  1989.  Chemical Information Service (CIS).  On-line: July  8,  1989.

Chlu, C.W., L.H. Lee,  C.Y. Wang  and  G.T.  Bryan.   1978.   Mutagenlclty of some
commercially  available nltro compounds  for  Sajmonella  typhlmurlum.   Hutat.
Res.  58: 11-22.

Crockett,  P.W.,  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  in the  Dose-Duration  Plane.  Prepared by  K.S. Crump and
Company,  Inc.,  under  Contract  No.  6807-007  for  the Environmental  Criteria
and Assessment Office, U.S. EPA, Cincinnati,  OH.

Dellarco, V.L.  and  M.J.  Prlval.   1989.   Hutagenlclty  of  nltro compounds  1n
Salmonella  typhlmurlum  In  the  presence  of  flavin   mononucleotlde  In  a
preincubatlon  assay.  Environ.  Mol. Mutagen.   13:  116-127.

Deneer,  O.W.,  T.L.  Slnnlge,  W.  Selnen and J.L.M. Hermens.   1987.   Quantita-
tive structure-activity  relationships  for the toxlclty  and bloconcentratlon
factor  of  nitrobenzene derivatives  towards  the guppy  (Poeclju retlculata).
Aquat. Toxkol.   10(2-3): 115-129.

Dunlap,  K.L.     1981.    Nitrobenzene  and  nitrotoluenes.   In.:  K1rk-0thmer
Encyclopedia  of  Chemical  Technology,  Vol.  15,  3rd ed.,  M.  Grayson and  D.
Eckroth, Ed.  John Wiley and Sons,  Inc., New York.  p.  923-924.

0318d                                -38-                             02/15/91

-------
Durkln,  P.  and  W.  Meylan.  1989.   User's  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,  Task
20   for   the  Environmental  Criteria  and   Assessment   Office,   U.S.   EPA,
Cincinnati, OH.

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

Ferro, D. and  V. Placente.  1985.  Heat of  vaporization of  o-,  m-,  p-nltro-
aniline.  Thermochim. Acta.  90: 387-389.

Garner,  R.  and  C.A.  Nutman.   1977.   Testing  of  some azo  dyes and  their
reduction  products   for  mutagenlclty  using  Salmonella  typhimurlum  TA1538.
Mutat. Res.  44: 9-19.

Gross, P.M.,  J.H.  Saylor  and M.A.  Gorman.   1933.  Solubility studies.   IV.
The solubilities of certain  slightly  soluble  organic compounds  In water.   J.
Am. Chem. Soc.  55:  650-652.

Hallas,  L.E.  and M.  Alexander.  1983.   Mlcrobial transformation of  nltro-
aromatic  compounds   in   sewage   effluent.   Appl.  Environ.  Hlcrobiol.    45:
1234-1241.

Hansch,  C.  and  A.J.  Leo.    1985.   Medchem Project.   Issue  No.   26.   Pomona
College, Claremont,  CA.
0318d
-39-
08/16/90

-------
Harris,  J.C.   1982.   Rate of hydrolysis,   in: Handbook of Chemical  Property
Estimation  Methods,  W.J.   Lyman,  W.F.   Reehl   and   O.H.   Rosenblatt,   Ed.
McGraw-Hill Book Co., New York.  p. 7-1  to 7-9.

Haskell  Laboratories.   1981.   Inhalation  Median  Lethal Concentration  (IC58)
EPA 878220247.  Fiche #215025.

Hawley,  G.G.    1981.   The  Condensed  Chemical   Dictionary,  10th  ed.   Van
Nostrand Relnhold Co., New York.  p. 730.

Houser,  R.M.,  L.D.  Stout and  W.E.  Rlbelln.   1983.  The  subchronk  toxlclty
of p-nltroanlllne administered  to male and female Sprague-Dawley  rats  for  90
days.  Toxlcologlst.  Abstr. of Annual  Meet.   3(1): 128.

KHano,  M.   1978.    Blodegradatlon and   bloaccumulatlon  test  on  chemical
substances.  OECD Tokyo Meeting.  Reference Book TSU-No. 3.

Kolodub,  F.A.  and  N.M.  Vasllenko.  1976.   Effect of mono- and  dlnltroanl-
llnes  on  oxidation  and  phosphorylatlon   processes  In the  liver  of  rats.
Deposited Doc. VINITI 1695-76.  10 p.

Kuney,  J.H.,  Ed.   1988.    Chemcyclopedla  1989,   Vol.  7.   American  Chemical
Society, Washington, DC.  p. 94.

Le, 0., R. Jung and  M.  Kramer.   1985.  Effects  of using liver  fractions  from
different  mammals,   Including man,  on  results   of  mutagenlcHy  assays  In
Salmonella typhlmurlum.   Food Chem. Toxlcol.   23(7):  695-700.

0318d                               -40-                              08/16/90

-------
Loeb,  H.A.  and W.H.  Kelly.   1963.   Acute  Oral  loxlclty of  1,496  Chemicals
Force-Fed  to Carp.   U.S.  Fish.  W1ldl.  Serv. Sp.  Set.  Rep.-Fish.   No.  471.
Washington, DC.  124 p.

Lyman,  W.J.   1982.   Adsorption  coefficient  for  soils  and sediments.   Ijn:
Handbook of  Chemical Property Estimation Methods,  W.J.  Lyman,  W.F.  Reehl  and
D.H. Rosenblatt, Ed.  McGraw-Hill Book Co.,  New York.  p. 4-1 to 4-11.

Malaney,  G.W.   1960.   Oxldatlve  abilities  of  aniline-acclimated  activated
sludge.  J. Water Pollut. Control Fed.  32:  1300-1311.

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

Mate,  C.,  A.J. Ryan  and  S.E.  Wright.  1967.   Metabolism  of  some  4-nltro-
anlllne derivatives 1n the rat.   Food Cosmet.  ToxUol.  5(5): 657-663.

Meljers,  A.P.  and  R.Chr.  Van  Der  Leer.   1976.   The occurrence of  organic
mlcropollutants In  the River Rhine and  the  River  Maas  In 1974.  Water  Res.
10: 597-604.

Mill,  T.  and W. Mabey.  1985.   Photochemical  transformations.   lr±:  Environ-
mental  Exposure from  Chemicals, Vol.  I, W.B.  Neely and G.E.  Blau,  Ed.   CRC
Press, Boca Raton, FL.  p. 208-210.
0318d                               -41-                             08/16/90

-------
Monsanto.   1983.   Letter of  December  12, 1983  from R.S.  Nalr St.,  Product
lexicologist,  Monsanto  Co.  to  W.B.   Pagageorge  about  ortho-nHroan1Hne
4-week  Inhalation  toxldty  study In male rats BD-82-270.  See  also  8081-32.
EPA 878214205.  Hebe #OTS0206486.

Monsanto.   1984.    Range finding   study  of   2-n1troan1l1ne  administered  by
gavage to pregnant rats.  EPA 878214236.   F1che #0750206497.   p. 1A-35.

Monsanto.   1985.    Orthonltro  aniline.   A   teratology  study  In  rats.   EPA
868600002.  F1che #0150510153.  p. 1A-30, 110-122.

Moskalenko,  E.G.    1966.    lexicological  characteristics   of   nHroanlllne
hygienic  basis  for  permissible  concentrations  of  nltroamlno  compounds  1n
reservoir waters.   Vopr. Kommunal'n. Gig.  6: 89-94.

NCI  (National  Cancer  Institute).   1985.  Monographs  on  Human Exposure  to
Chemicals  1n  the  Workplace: NHroanlUnes.    (Final  Draft).  National  Cancer
Institute, Bethesda, MD.  p. 3-1 to 3-2.

NIOSH  (National   Institute   for  Occupational  Safety   and   Health).    1989.
National  Occupational  Exposure  Survey  (NOES).   Computer printout:  3-29-89.
Cincinnati, OH.

Northcott, J.  1978.  Amines,  aromatic  (anilines).   In:  Klrk-Othmer  Encyclo-
pedia of  Chemical  Technology,  Vol.  2,  3rd   ed.,  M.  Grayson  and D.  Eckroth,
Ed.  John Wiley  and Sons, Inc., New York.  p. 319.
0318d
-42-
08/16/90

-------
Parrls,  G.E.   1980.   Covalent  binding of  aromatic  amines  to  humates.   1.
Reactions  wHh  carbonyls  and   qulnones.   Environ.  Sd.  Technol .    14(9):
1099-1106.

Perrin,  D.D.   1964.   The  effect  of  temperature of  PK  values  of  organic
bases.  Aust.  J.  Chem.  17: 484-488.

PHter,  P.    1976.    Determination  of  biological  degradablllty  of  organic
substances.   Water Res.  10: 231-235.

RTECS  (Registry   of   Toxk  Effects  of  Chemical  Substances).   1975.   H.E.
Chrlstenson,  T.T.  Luglnbyhl,  Ed.  U.S.  Department  of  Health, Education  and
Welfare, Rockvllle, MD.  (Cited 1n  Watanabe et al.,  1976)

Sasaki, S.  1978.  The scientific aspects  of  the  chemical  substances  control
law  1n  Japan.   ITK  Aquatic  Pollutants.   Transformation  and   Biological
Effects, 0.  Hutzlnger, L.H. Von  Letyueld and  B.C.J.  Zoetemazn, Ed.   Pergamon
Press, Oxford,  p. 283-298.

Schafer, E.W., Jr.,  W.A.  Bowles, Jr.  and  J.  Hurlbut.  1983.  The  acute oral
toxlclty, repel lency  and  hazard potential  of 998 chemicals  to  one  or  more
species of wild and  domestic  birds.   Arch.  Environ.  Contam.  Toxlcol.   12(3):
355-382.

Schultz,  T.W.  and  F.M.   Applehans.    1985.    Correlations  for   the  acute
toxlclty  of  multiple  nitrogen  substituted aromatic  molecules.   Ecotoxlcol.
Environ. Saf.   10: 75-85.
0318d                               -43-                             08/16/90

-------
 Shlmlzu,  H.  and  N.  Takemura.   1983.   Mutagenlclty  of some  anallne  deriva-
 tives.   In.:  Occupational  Health 1n the Chemical  Industry,  R.R,  Orford,  J.W.
 Cowell,  G.G. Jamison and G.3. Love, Ed.  MEDICHEM, Edmonton,  p. 497-506.

 Shlmlzu,  M.  and  E.  Yano.   1986.   Mutagenlclty  of  mononltrobenzene  deriva-
 tives In the Ames test and rec assay.  Hutat. Res.  170(1-2): 11-22.

 SRI  (Stanford  Research  Institute).   1983.   Evaluation  of  the  Potential  of
 o-N1troan111ne to Induce  Unscheduled  DNA  Synthesis  In Primary Rat Hepatocyte
 Cultures, with cover memo and sheet.  EPA 878214903.  Flche No. OTS0206696.

 SRI  (Stanford  Research  Institute).   1989.   1989  Directory  of  Chemical
 Producers: United States of America.   SRI  International,  Menlo  Park,  CA.
 p. 370, 805.

 Steadman,  T.R.,   E.W.  Helper,  T.  Parsons,  G.E.  W1lk1ns  and  N.P.  Phillips.
 1977.   Industrial Process  Profiles for Environmental  Use.   Organic  Dyes and
 Pigments Industry.  EPA 600/2-77-023g.  NTIS PB281-479.  p. 68-69.

 Swann,  R.L., D.A. Laskowskl,  P.J.  McCall, K. Vanderkuy and H.J.  Olshburger.
 1983.   A rapid method for  the  estimation  of  the  environmental  parameters
 octanol/water  partition  coefficient,  soil  sorptlon  constant,  water  to air
 ratio, and water  solubility.   Res.  Rev.  85: 17-28.

Thomas,  R.G.   1982.   Volatilization  from water.   In.:  Handbook  of  Chemical
 Property Estimation Methods, W.J.  Lyman,  W.F. Reehl  and  O.K. Rosenblatt, Ed.
McGraw-Hill Book Co., New York.   p. 15-1 to 15-34.
0318d
-44-
08/16/90

-------
 Thompson,  C.2.,  L.E. Hill,  J.K.  Epp and G.S.  Probst.   1983.   The Induction
 of  bacterial  mutation   and  hepatocyte  unscheduled  DNA  synthesis by  mono-
 substituted anilines.  Environ. Mutagen.  5(6): 803-811.

 Toxic  Substances  List.    1974.   H.E. ChMstensen,  T.T.  Luglnbyhl,  Ed.   U.S.
 Department  of  Health,   Education   and  Welfare,  Rockvllle,  MD.    (Cited  1n
 Watanabe et al., 1976)

 Urano,  K.  and  Z.   Kato.   1986.    Evaluation  of  blodegradatlon  ranks  of
 priority organic compounds.  J. Hazard. Mat.  13:  147-159.

 U.S.  EPA.   1980.   Guidelines  and  Methodology  Used  1n  the Preparatalon  of
 Health  Effect  Assessment Chapters of  the  Consent   Decree  Water  Criteria
 Documents.  Federal Register.  45(231): 79347-79357.

 U.S. EPA.   1984.   Methodology  and  Guidelines for Ranking  Chemicals Based  on
 Chronic Toxlclty  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.   1985.  Health  and Environmental  Effects  Profile for  NHroanlllne.
 Prepared by the Office of Health  and Environmental  Assessment,  Environmental
 Criteria and Assessment Office, Cincinnati,  OH  for  the  Office  of  Solid  Waste
 and Emergency Response.   EPA/600/X-85/115.   MTIS PB88-180443/AS.
0318d                               -45-                             08/16/90

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

U.S. EPA.  1989.  STORE! Water Quality Database.   Online: July, 1989.

U.S. EPA/OWRS  (U.S.  Environmental Protection Agency/Office of  Water Regula-
tions  and  Standards).   1986.   Guidelines  for  Deriving  Numerical  National
Water  Quality  for  the  Protection  of  Aquatic   Organisms and  Their  Uses.
Washington, DC.  GRAI8522.

USITC  (U.S.   International  Trade  Commission).    1989.   Synthetic  Organic
Chemicals:  United  States  Production  and  Sales,  1988.   USI1C Publ.  2219,
Washington, DC.  p. 3-2, 3-11.

Vasllenko,  N.M.,  V.I. Zvezdal and  I.I.  Kovalenko.   1972.  Inaction of  the
blood  respiratory  pigment  under  the  effect  of  aromatic nltro  and  amlno
compounds  from  the benzene  series.   Sovrem.  Prob. Blokhlm.  Dyhanlya Klin.,
Mater.  Vses.  Knof.   1: 411-413.                                       '

Vasllenko,  N.M.,   V.I.  Zvezdal and  F.A. Kolodub.   1974.  Toxic  action  of
raonon1troan1l1ne Isomers.   Gig. SanH.  8: 103-104.
0318d
-46-
08/16/90

-------
Watanabe,  T.,  N.  Ishlhara and  M.  Ikeda.   1976.  ToxIcHy of  and  biological
monitoring   for  1,3-d1am1no-2,4-6-trInltrobenzene   and   other   nltroamlno
derivatives  of  benzene  and  chlorobenzene.   Int.  Arch.   Occup.  Environ.
Health.  37(3): 157-168.

Weast,  R.C.,  Ed.   1985.   CRC  Handbook  of  Chemistry  and  Physics, 66th  ed.
CRC Press, Inc., Boca Raton, FL.  p. C-73.

Wlndholz,  M.,  Ed.   1983.   The Merck Index,  10th ed.   Merck  and  Co.,  Rahway,
NJ.  p. 944-945.

Wooster, C.B.   1963.  Ammonolysls.   lr\: Klrk-Othmer  Encyclopedia of Chemical
Technology, Vol. 2, 2nd ed.,  A.  Standen, Ed.   John  Wiley and Sons, Inc.,  New
York.  p. 352-353.

Yoshlml,  N.,   S.  Sugle,  H.   Iwata,  et al.    1988.   The  genotoxUHy  of a
variety  of  aniline  derivatives  In  a DNA  repair  test with  primary cultured
rat hepatocytes.  Mutat. Res.  206(2):  183-191.

Young,  J.C.  and S.B.  Affleck.  1974.  Long-term  blodegradablHty tests on
organic  Industrial  wastes.   Eng.   Bull  Purdue  Univ., Eng.  Ext.   Ser.   1:
154-164.

Younger  Laboratories.    1977.   Toxlclty   Study  of  o-N1troanH1ne.    EPA
878211624.   Flche #206222.
0318d                               -47-                             08/16/90

-------
 Zeyer,  J.  and  P.C.  Kearney.   1983.   Mlcroblal  metabolism of  [14C]n1tro-
 annines  to  [i4C]carbon dioxide.  J. Agrlc. Food Chem.  31: 304-308.

 Zoeteman,  B.C.J.,  K.  Harmsen, J.B.H.J. Unders, C.F.H. Morra and  W.  Slooff.
 1980.   Persistent  organic  pollutants In river water  and  ground  water  of the
 Netherlands.  Chemospfiere.  9: 231-249.
0318d
-48-
08/16/90

-------
                                  APPENDIX A

                              LITERATURE SEARCHED



    This  HEED   is  based  on  data  Identified  by  computerized  literature

 searches  of  the  following:


              CHEMLINE
              TSCATS
              CASK online  (U.S. EPA Chemical Activities Status Report)
              TOXLINE
              TQXltT
              TOXLIT 65
              RTECS
              OHM TADS
              STORET
              SRC Environmental Fate Data Bases
              SANSS
              AQUIRE
              TSCAPP
              NTIS
              Federal Register
              CAS ONLINE (Chemistry and Aquatic)
              HSD8
              SCISEARCH
              Federal Research In Progress


 These  searches  were  conducted In  July,  1989,  and  the  following  secondary

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

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

    Clayton,  G.O.  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.
0318(1                               -49-                             08/16/90

-------
    Clayton,  G.D.  and  F.E.  Clayton,  Ed.    1982.   Patty's  Industrial
    Hygiene  and  Toxicology,  3rd  rev.  ed.t  Vol.  2C.   John  Wiley  and
    Sons, NY.  p. 3817-5112.

    Grayson,  M.  and D.  Eckroth,  Ed.   1978-1984.   Klrk-Othmer  Encyclo-
    pedia of  Chemical  Technology,  3rd  ed.   John  WITey 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.

    Oaber,  H.M.,  W.R.  Mabey,  A.T.  Lieu,  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,   Menlo
    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   1n  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., 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.
0318d
08/16/90

-------
    In  addition,  approximately  30  compendia of  aquatic  toxlclty  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  ToxIcHy
    of  Chemicals  to  Fish  and  Aquatic   Invertebrates.   Summaries  of
    ToxIcHy  Tests  Conducted  at Columbia  National Fisheries  Research
    Laboratory.   1965-1978.   U.S.  Dept.  Interior, Fish  and  Wildlife
    Serv. Res. Publ. 137,  Washington, DC.

    McKee,  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, B.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.
0318d                               -51-                             08/16/90

-------






















01
c
•r—
i— •
•£

Iw.
(Q
g
E
3
C/5


































01
U
c

<
4J
o
M-
u-
LU















O)
3
I/)
O
Q.
X
LU










I/I
0)
»^™
OJ
d.
C/5


















t/l
U
^m,,.
E
"3
i^^ ^3
-x CO
0 03
00 i—
n
£
E

C^
o
(^
0
LU >>
"(O O •»-
U Z 0
0 T-
i — •« X
C 0
1_ O *->
o •«- o
u- -4-1 E
ro a>
LU f-

O 1_ O
_l 1- <*-


t/1
(U
o>
x^ 35
i/1
« ^^ *•"•*"
3 n
o i_ E
J= O -x,
v£> "" 1°
^^
t- O) CO
O (U *
Q. 3 ^«
"0 ^x
> i/> II
^^
n> 03 / ^
E X! LU
OILO _j
E '• -•'
n ^C
CO >>O
• "3 _!
cn T3 • — •



%
k.


0)
t-
3
I/I
O
a
X
UJ
C U
o «-
*- c
— > 0
<"O ^
^^ ^^
*O tJ
g* jmD
c r>
1—1 CO
i/r
tj
f~*
E
.
X. CO
0 CO
CO •— Z



CNJ
CO n
o E
0 X.
fc=
>-•
LU >l
^ C? •*—
u Z u
0 —
i — •• X
C 0
4_ O •*••
o •»- o
u- -t-> E
IT) 0)
LU *•
<£ 1_ L.
0 1_ 0 0
_J f U- 1— 1


uo
a>
O)
V. 3

^_ ^* ^**
3 n
o L. E
JZ O "X
**•?
XX
i- at co
o a> •
Q. 3 i—
ro V.
> tf> il
^^
n 03 c_)
E T3 LU
aiLn — i
E LU

OO >">O
• ^ ^^ r*^
en -o — —



/i on CO
0 u CO
•r* ^__ —^
E E .-

C C «
"X, CO "N, CO is\ f^
O GO O GO ZJ
! >,
^O L^ ^3
kO -x O V.
CO O5 CO CJ?
O J^ O H
o \ o \
• 7) • Q) O
o e o e i—



^*> >>
-fcJ ^— »
H— -r—
^ t
O O
LU O LU O
> ai >» at
03 aj 
T3 3 "O 3
'vT -> 3 L» >>
O O fT3 O O ro
jmH ^_  j* CD _i£
PI Cf "**»•» <*1 Q^ "^v
e 3 o> E 3 a>
O> I/I Q) I/I
E >>co E >>ao
(O LT> to U1
CO T3 • OO -O • O
• O • O G O ^
CT» LT1 -^ — i t— i"^

. ,
>>
^O "fO Q ^ -2*
l_ t_ l— i o t—

t— (J 0
>• Z i- C
•*-• « C t-
•*- 3 O (J
U O 4- i-
U C LU U CJ
•^ C^ J
C O> DO C C
o u o «t o o
l_ -- C I—
jz c i- as -a -a
u o u o a> ai
-Q L. 4- O- 4rt t/l
3 JZ ra LU PO "3
oo o cj as ao co














































-------
                                  APPENDIX C
         DOSE/DURATION RESPONSE GRAPHS FOR EXPOSURE TO 2-NITROANALINE
C.I.   DISCUSSION
    Dose/duration-response  graphs   for   Inhalation  and  oral  exposure  to
2-nltroanlllne, generated  by  the  method of Crockett  et  al.  (1985) using the
computer  software  by Durkln  and  Meylan  (1989)  developed under  contract  to
ECAO-C1nc1nnat1, are presented  In  Figures C-l  through  C-4.   Data  used  to
generate  these graphs are  presented in  Section  C.2.  In the  generation  of
these  figures,  all  responses are classified  as adverse  (PEL,  AEL or LOAEL)
or  nonadverse  (NOEL  or   NOAEL)   for   plotting.    The  ordlnate  expresses
Inhalation exposure  In  either of  two ways.   In  Figure  C-l,  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
expanded   experimental   concentration   [expanded   exp   cone   (mg/m3)].    In
Figure  C-2,  the expanded  experimental  concentration was multiplied  by the
animal  Inhalation  rate  1n  mVday  and divided  by  the animal  body weight  1n
kg  to  calculate   a  dally dose  In  mg/kg/day.   The  dally   dose was  then
multiplied by  the  cube  root of the  ratio  of  the  animalihuman body weight  to
adjust  for  species differences  In  metabolic  rate  (Mantel and Schnelderman,
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 mg/day
for a  70  kg  human  [human equivalent dose  (mg/day}].   For oral exposure, the
ordlnate  expresses  dose  as  human  equivalent  dose.   The   animal  dose  In
mg/kg/day  Is  multiplied  by  the cube root of  the  ratio  of  the animal:human
body  weight   to adjust  for  species  differences   In basal  metabolic  rate
0318d                               -53-                             08/16/90

-------
      10000
 I

 *
 *

 V

 M

 I
 X
 ill
 A
 *
 •
 z
          0.001
(Inhalation  Exposure)
HUMRN EQUIU  DUBflTION (fraction lifespan)

           ENUELOP METHOD
       Key:     L -  LOAEL
               n «  NOAEL
               Solid  Une  »  Adverse  Effects  Boundary
               Dashed  line » No  Adverse  Effects  Boundary
                                   FIGURE C-l

    Dose/Duration-Response  Graph  for  Inhalation  Exposure  to  2-NUroan1l1ne:
              Envelope Method  (Expanded  Experimental  Concentration)
 0318d
         -54-
08/16/90

-------
  f
  £
 v
 111

 I
 to
       1008 r
    L

160 r

    fc
         10 t

            i.
          1
                     X..
                      !       1    1
          e.eei


(Inhalation  Exposure)
                                        1  1  I  t
                                                                        ~\—r
                                                           •F>4


                                                            nl
                 0.01

HUMflN EQUIU DURRTION (fraction lifespan)

           ENUELOP  METHOD
                                                                          0.1
     Key:     L • LOAEL
             n » NOAEL
             Solid line « Adverse Effects Boundary
             Dashed line « No Adverse Effects Boundary
                                      FIGURE  C-2

       Dose/Duration-Response Graph for Inhalation Exposure  to 2-NHroanlllne:
                       Envelope Method (Human Equivalent Dose)
   0318d
                                -55-
                                            08/16/90

-------
 V
 c
 A

          8.0001


(Oral  Exposure)
                                 Fl


                                 fl2

                                  F4


                                 43
                                                              iti6
     0.001                   6.01

HUhRN EOUIU  DURRTION (fraction lifespan)

           ENUELOP METHOD
         0.1
      Key:    F
              A « AEL
              L - LOAEL
              n . NOAEL
              Solid line » Adverse Effects Boundary
              Dashed line - No Adverse Effects Boundary

                                    FIGURE C-3

      Dose/Duration-Response Graph for Inhalation Exposure to 2-NUroanlllne:
                                  Envelope Method
  0318d
          -56-
08/16/90

-------
\
9
r.'
M
     18888 ^
      1088
Oral Exposure)
                                          1    I   I   1  1 i I  1

                                 Fl


                                 R2

                                  F4
                                                             --t5-
                  1    i   1
                                              i   1  1
                                                             -p6
                                                                 j	I
     0.801                   0.01
HUflflN EQUIU DURflTION (fraction lifespan)

      CENSORED DRIfl METHOD
                                                                                 0.1
    Key:     F » FEL
             A - AEL
             L - LOAEL
             n « NOAEL
             Solid  line  -  Adverse  Effects Boundary
             Dashed  line • No Adverse Effects Boundary
                                   FIGURE C-4

    Dose/Duration-Response Graph  for  Inhalation Exposure to 2-N1troan1l1ne:
                                Censored Method
0318d
         -57-
08/16/90

-------
 (Mantel  and Schnelderman,  1975).   The result  Is  then multiplied by  70  kg,
 the  reference human  body weight,  to  express  the  human equivalent  dose  as
 mg/day for  a 70 kg human  [human equlv dose (mg/day)].
    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  Is  extended  upward parallel  to  the  dose axis.   The  starting
 point  1s  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  1s  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)
 1s drawn starting with  the  point  representing the  highest  no adverse effects
 dose  or  concentration.   From this  point,  a  line  parallel  to  the  duration
 axis  1s  extended  to  the  dose or  concentration axis.   The starting  point  Is
 then  connected to  the next equal or lower no adverse  effect  dose or  concen-
 tration at  a longer  duration  of  exposure.   When this  process  can no longer
 be continued,  a  line parallel to  the  dose or  concentration axis Is  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 Is defined as  the region of contradiction.
    In the  censored  data  method,  all no adverse effect points  located 1n  the
region of  contradiction  are  dropped  from consideration and  the  no  adverse
0318d
-58-
08/16/90

-------
effects  boundary  Is  redrawn  so  that  It  does  not  Intersect  the  adverse
effects  boundary and no  region of contradiction Is  generated.   This method
results  In  the most  conservative definition of the no adverse effects region.
    figure  C-l  represents  the (lose/duration-response  graph  of Inhalation
data  expressed  as   expanded  concentrations  and generated  by  the  envelope
method.   The  boundary  for adverse  effects  1s  defined  by  two  points  (B1o/
Dynamics,  1983a):  LOAELs  In  rats  for  transient  corneal opaclf1cat1on  In  a
single  4-hour  exposure  (Rec.  #6,  Section  C.2.1.)  and  for  hemotoxIcHy  In
rats  exposed  for   4 weeks   (Rec.   #3,  Section  C.2.I.).   Rec.   #5  (Section
C.2.I.),  a  PEL  for  lethality In  rats exposed for 4  hours  was  not displayed
because  It  would  obscure  Rec. #6  (Section  C.2.I.).   The  boundary for  no
adverse  effects  1s  defined  by a  NOAEL  (Rec.  #4, Section  C.2.1.)  for  nemo-
toxlclty  In  the  same study.  The  large region  of ambiguity results  from the
paucity  of  the  database.   Figure C-2 represents  the  graph  for  the same data
set  expressed  as   the  human  equivalent  dose  and  graphed  by  the  envelope
method.
    Figure  C-3  represents  the dose/duration-response  graph  of oral  data
generated  by   the  envelope  method.   The   boundary  for   adverse effects  Is
defined  by  FELs  for  LD™ values  In  guinea pigs (Rec.  #11,  Section  C.2.2.)
and  rats (Rec.  #8,  Section  C.2.2.),  and  a  LOAEL   for  transient signs  of
maternal toxlclty In  a gavage study  In  rats (Rec. #5, Section C.2.2.).   Rec.
#10  (Section  C.2.2.), an LD5Q  1n mice,  was  not plotted  because It  would
obscure  rec.  #11  (Section  C.2.2.).   The  boundary   for  no adverse  effects
passes  through   two  points,   both  of  which are  NOAEls  for  fetotoxlclty  and
maternal  toxlclty  In pregnant  rats   (Recs.  #3  and  6, Section  C.2.2.).   The
small  region  of  contradiction  probably arises  from  the choice  of doses  In
the two  developmental  toxlclty studies  In  rats  (Monsanto,  1984,  1985).   The
0318d
-59-
08/16/90

-------
region  of  contradiction  Is  eliminated  using  the  censored  data  method  In
Figure  C-4,  In which  the  no  adverse effects boundary passes only  the  NQAEL
of  Rec. #6  (Section C.2.2.)  (Monsanto,  1985).  None  of these records  are
derived  from exposures  of  sufficient duration  and presented  \n  sufficient
detail  to be  the  basis  for  an  RfD;  therefore, a  subchronlc  oral  RfD  was
derived from Inhalation data (Rec. #1, Section C.2.I.).
C.2.   DATA USED TO GENERATE DOSE/DURATION-RESPONSE  GRAPHS
C.2.1.   Inhalation Exposure.
Chemical Name:    2-N1troan1lIne
CAS Number:       88-74-4
Document Title:   Health and Environmental Effects Document on 2-NHroanll1ne
Document Number:  Pending
Document Date:    Pending
Document Type:    HEED
RECORD #1: Species: Rats
Sex: Male
Effect: LOAEL



Route: Inhalation





Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:





10
5
IRRIT
NASAL
2
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Weight:
Inhalation hours/day:
Inhalation days/week:
# Inhal . Exp. days:





0.35 kg
9.8 mg/m3
1 .75 mg/m3
4 weeks
4 weeks

6.00
5.00






Comment:
Citation:
Exposed  to  0,  9.8,  93 mg/m3  aerosol/vapor  6  hours/day,  5
days/week.  Nasal  Irritation,  lacrlmatlon;  this  value  1s  also
a  NOAEL  for   hemotoxldty   (see   next   record).   Basis   for
subchronlc Inhalation and oral RfDs.
B1o/Dyanamics, 1963b
03180
                     -60-
08/16/90

-------
RECORD #2;
Species:
Sex:
Effect:
Route:
Rats
Hale
LOAEL
Inhalation
Body Weight:          0.35 kg
Reported Dose:        93 mg/m3
Converted Dose:       16,6 mg/m;
Exposure Period:      4 weeks
Duration Observation: 4 weeks
Molecular Weight:
Inhalation hours/day: 6.00
Inhalation days/week: 5.00
# Inhal. Exp. days:


Comment :
Citation:
RECORD #3:



Comment:

Citation:
Number Exposed: 10
Number Responses: 5
Type of Effect: IRRIT
Site of Effect: NASAL
Severity Effect: 2
10
NR
HEMAT
BLOOD
7


See previous record; methemogloblnemla.
Blo/Dyanamlcs, 1983b
Species: Rats
Sex: Both
Effect: LOAEL
Route: Inhalation

Number Exposed: 20
Number Responses: NR
Type of Effect: IRRIT
Site of Effect: NASAL
Severity Effect: 2

Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Weight:
Inhalation hours/day:
Inhalation days/week:
Inhal. Exp. days:
20
NR
HEMAT
BLOOD
7
Exposed to 0, 10, 28, 73 mg/m3 aerosol/vapor 6
days/week. Nasal Irritation, lacrlmatlon,
testlcular effects 1n males attributed to
(vehicle).
B1o/Dynam1cs, 1983a



0.2721 kg
73 mg/m3
13 mg/m3
4 weeks
4 weeks
6.00
5.00


hours/day, 5
hemotoxldty;
cellosolve


0318d
                     -61-
                                           08/16/90

-------
 RECORD #4;
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Both
NOAEL
Inhalation
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Weight:
Inhalation hours/day:
Inhalation days/week:
Inhal. Exp. days:
0.2721  kg
28 mg/rn3
                                                                    mg/m3
                                                                    weeks
                                                                    weeks

                                                                    00
                                                                    .00
Number Exposed:     20
Number Responses:   NR
Type of Effect:     IRRIT
Site of Effect:     NASAL
Severity Effect:    2

See previous record; nasal  Irritation,  lacrlmatlon;  this  value
1s  also  a  NOAEL   for   hemotoxidty   In  this  study.   At  10
mg/m3, only effect was yellow discoloration of fur.

Bio/Dynamics, 1983a
RECORD #5: Species: Rats
Sex: Male
Effect: PEL
Route: Inhalat





Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:



1on





10
3
DEATH
BODY
10
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Weight:
Inhalation hours/day:
Inhalation days/week:
# Inhal . Exp. days:
10 10 10
NR NR NR
0.245 kg
7.55 mg/i
7550 mg/m3
1 days
14 days

4.00
1.00



WGTIN WGTIN DEGEN
LIVER LUNG EYE
445


Comment:       Exposed  to  1.1,  6.53,  6.61,
               mg/i  vapor  and aerosol.  Not
               Lowest lethal concentration.

Citation:      Haskell Laboratories, 1981
                              7.55,  8.66, 8.96,  11.66,  12.02
                              expanded to  continuous  exposure.
0318d
                     -62-
                                           08/16/90

-------
RECORD #6;
Comment:

Citation:
Species:
Sex:
Effect:
Route:
Rats
Male
LOAEL
Inhalation
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
Molecular Height:
Inhalation hours/day:
Inhalation days/week:
# Inhal. Exp. days:
0.245 kg
6.61 mg/2.
6610 mg/m3
1 days
14 days

4.00
1.00
Number Exposed:     10
Number Responses:   NR
Type of Effect:     DEGEN
SHe of Effect:     EYE
Severity Effect:    5

Details 1n previous record.   Transient corneal  opadfIcatlon.

Haskell Laboratories, 1981
C.2.2.  Oral Exposure.
Chemical Name: 2-NHroanlllne
CAS Number: 88-74-4
Document Title: Health and Environmental Effects Document on 2-NHroan1l1ne
Document Number: Pending
Document Date: Pending
Document Type: HEED
RECORD #1: Species:
Sex:
Effect:
Route:


Rats
Female
FEL
Gavage


Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:

0.2755 kg
1200 mg/kg/day
1200 mg/kg/day
10 days
16 days
               Number Exposed:
               Number Responses:
               Type of Effect:
               Site of Effect:
               Severity Effect:
                    6666
                    45       NR      NR
                    DEATH  NEUR8   WGTDC   WGTDC
                    BODY   CNS     FETUS   BODY
                    10     9       8       4
Comment:
CHatlon:
Dosed  0,  50,  200,  400,  800,   1200
6-15.  Maternal  death,  CNS  signs.
probably from maternal toxlclty.

Monsanto,  1984
                          mg/kg/day  gestation  days
                          Reduced fetal body weight
0318d
                     -63-
                                           08/16/90

-------
 RECORD #2;
Comment:
Species:
Sex:
Effect:
Route:
Rats
F ema1e
AEL
Gavage
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
0.2852 kg
800 mg/kg/day
800 mg/kg/day
10 days
                                          Duration Observation: 16 days
               Number Exposed:
               Number Responses:
               Type of Effect:
               Site of Effect:
               Severity Effect:
                    666
                    1       NR      NR
                    NEURB  WGTOC   MGTOC
                    CNS    FETUS   BODY
                    7       8       4
Protocol  1n
gasping  for
Reduced mean
    previous   record.    Dams  lethargic,   unsteady,
   air,   decreased  weight  gain,  food  consumption.
  fetal  weight probably due to maternal  toxldty.
Citation:
RECORD #3:
Monsanto,
Species:
Sex:
Effect:
Route:
1984
Rats
F ema 1 e
NOAEL
Gavage

Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:

0.2897 kg
400 mg/kg/day
400 mg/kg/day
10 days
16 days
               Number Exposed:     6
               Number Responses:   6
               Type of Effect:     PIGMN
               Site of Effect:     SKIN
               Severity Effect:    1
Comment:
Citation:
Details In previous record; discolored fur reported 1n all
exposed groups.
Monsanto, 1984
RECORD #4: Species: Rats
Sex: Female
Effect: FEL
Route: Gavage

Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:





25
NR
WGTDC
BODY
4
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
0
2
TERAS
FETUS
9
0.2897 kg
600 mg/kg/day
600 mg/kg/day
11 days
16 days





Comment:       Dosed  0,   100,   300,   600  mg/kg/day  gestation  days   6-15.
               Decreased maternal  body weight  gain, food  consumption   Situs
               Inversus 1n one fetus 1n each of two litters.

Citation:      Monsanto, 1985
0318d
                     -64-
                                           08/16/90

-------
RECORD #5:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
F ema1e
LOAEL
Gavage
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
0.28232 kg
300 mg/kg/day
300 mg/kg/day
11 days
                                          Duration Observation: 16 days
Number Exposed:     25
Number Responses:   NR
Type of Effect:     70XSL
Site of Effect:     OTHER
Severity Effect:    4

Protocols  In  previous  record.   Transient plloerectlon,  pale,
cold  extremities.    Reduced  food  consumption.   Yellow-orange
stains body, urine.  No fetal effects.

Monsanto, 1985
RECORD #6:









Comment :
Citation:
RECORD #7:









Comment:
Citation:
Species: Rats
Sex: Female
Effect: NOAEL
Route: Gavage

Number Exposed: 25
Number Responses: 25
Type of Effect: PIGMN
SHe of Effect: OTHER
Severity Effect: 1
Details previous record.
Monsanto, 1985
Species: Rats
Sex: Both
Effect: PEL
Route: Oral (NOS)

Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: BODY
Severity Effect: 10
1050 study.
Younger Laboratories, 1977
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:







Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:







0.28108 kg
100 mg/kg/day
100 mg/kg/day
11 days
16 days







0.35 kg
2050 mg/kg/day
2050 mg/kg/day
1 day
1 day







0318d
                     -65-
                                           08/16/90

-------
RECORD #8:
Comment:
Citation:
RECORD #9:

Comment:
Citation:
RECORD #10:

Comment:
Citation:
Species: Rats
Sex: NR
Effect: PEL
Route: Oral
Number Exposed:
Number Responses
Type of Effect:
Site of Effect:
Severity Effect:
LDso study.
Toxic Substances
Species: Rats
Sex: NR
Effect: PEL
Route: Oral
Number Exposed:
Number Responses
Type of Effect:
SHe of Effect:
Severity Effect:
LDso study.
Vasllenko et al.
Species: Mice
Sex: NR
Effect: PEL
Route: Oral
Number Exposed:
Number Responses
Type of Effect:
Site of Effect:
Severity Effect:
LDso study.
Moskalenko, 1966
Body Weight:
Reported Dose:
Converted Dose:
(NOS) Exposure Period:
Duration Observation:
NR
: NR
DEATH
BODY
10

List, 1974; RTECS, 1975
Body Weight:
Reported Dose:
Converted Dose:
(NOS) Exposure Period:
Duration Observation:
NR
: NR
DEATH
BODY
10

, 1974
Body Weight: 0
Reported Dose: 1
Converted Dose: 1
(NOS) Exposure Period: 1
Duration Observation: 1
NR NR NR
: NR NR NR
DEATH NEURB SUBCC
BODY MSKEL RBC
10 7 2


0.35 kg
535 mg/kg/day
535 mg/kg/day
1 day
1 day




0.35 kg
3520 mg/kg/day
3520 mg/kg/day
1 day
1 day






.03 kg
246.1 mg/kg/day
250 mg/kg/day
day
day
NR
NR
HEMAT
LYM
6





0318d
-66-
08/16/90

-------
RECORD #11:    Species:   Guinea pigs   Body Weight:          0.84 kg
               Sex:       NR            Reported Dose:        2350 mg/kg/day
               Effect:    PEL           Converted Dose:       2350 mg/kg/day
               Route:     Oral {NOS}    Exposure Period:      1 day
                                        Duration Observation: 1 day

               Number Exposed:          NR       NR       NR       NR
               Number Responses:        NR       NR       NR       NR
               Type of Effect:          DEATH    NEURB    SUBCC    HEHA1
               Site of Effect:          BODY     MSKEL    RBC      LYM
               Severity Effect:         10       7        2        6

Comment:       1059 study.

Citation:      Moskalenko, 1966
NR = Not reported
0318d                               -67-                             08/16/90

-------

-------