United States
           Environmental Protection
           Agency
500ECAOCING003
EPA      Research and
           Development
           HEALTH AND ENVIRONMENTAL  EFFECTS DOCUMENT
           FOR CHLOROANILINES
           Prepared for
           OFFICE OF SOLID HASTE AND
           EMERGENCY RESPONSE
          —.         . .              Do^.   ,    	 Protection

          Prepared by           S^t£SBm street

          Environmental Criteria  and AsW's'SRrtfnf°0flice
          Office of  Health and Environmental Assessment
          U.S. Environmental  Protection  Agency
          Cincinnati, OH  45268


                      DRAFT: DO NOT CITE OR QUOTE


                              NOTICE

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

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                                  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

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                                    PREFACE
    Health  and  Environmental  Effects Documents  (HEEDs) are  prepared  for the
Office  of  Solid Haste and Emergency Response  (OSWER).  This document series
1s  Intended  to  support  listings  under  the Resource Conservation and Recovery
Act  (RCRA)  as well as  to provide health-related  limits and goals  for emer-
gency  and  remedial actions  under the  Comprehensive  Environmental  Response,
Compensation  and  Liability   Act   (CERCLA).   Both  published  literature  and
Information  obtained  from Agency Program Office  files  are  evaluated  as  they
pertain  to  potential  human health,  aquatic  life and environmental effects of
hazardous  waste constituents.  The literature  searched for  1n this document
and  the dates  searched  are  Included  1n "Appendix:  Literature  Searched."
Literature  search  material  1s 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 (RfDs)
for  chronic  and  subchronlc  exposures   for  both  the Inhalation  and  oral
exposures.   The subchronlc  or  partial  lifetime  RfD,  1s  an  estimate  of an
exposure  level   that  would  not  be  expected to -cause adverse  effects  when
exposure occurs  during  a limited  time  Interval,  for  example,  one  that  does
not constitute  a significant  portion of the  Hfespan.  This type of exposure
estimate has not  been  extensively used, or rigorously defined  as previous
risk   assessment   efforts  have   focused primarily   on   lifetime  exposure
scenarios.   Animal data  used  for  subchronlc  estimates   generally  reflect
exposure durations of  30-90  days.  The  general  methodology  for estimating
subchronlc RfDs  1s  the  same  as  traditionally employed for  chronic estimates,
except that  subchronlc data are utilized when available.

    In  the  case  of   suspected   carcinogens,   RfDs   are  not  estimated.   A
carcinogenic  potency  factor,  or  q-|*  (U.S.  EPA,  1980), 1s  provided Instead.
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.

    Reportable  quantities  (RQs)  based  on both  chronic  toxldty and carclno-
genlclty are  derived.   The  RQ Is used  to determine the quantity of a hazar-
dous substance  for  which  notification   1s required 1n the  event of a release
as specified under  the CERCLA.   These  two RQs  (chronic toxldty and carclno-
genlclty) represent two of  six  scores  developed (the remaining four reflect
1gn1tab1l1ty, reactivity,  aquatic  toxldty, and  acute mammalian toxlclty).
Chemical-specific RQs  reflect the  lowest  of  these six primary criteria.  The
methodology  for  chronic  toxldty  and  cancer-based RQs  are defined  1n  U.S.
EPA, 1983 and 1986a, respectively.
                                      111

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                              EXECUTIVE SUMMARY

    2-Chloroan1l1ne (CAS number 95-51-2) 1s an amber  liquid; 3-chloroan1l1ne
(CAS number 108-42-9) 1s a colorless to light amber liquid; and 4-chloroan1-
Une (CAS  number  106-47-8)  Is  a white to pale yellow solid at room tempera-
ture (Hawley, 1981).  They  are  slightly  soluble  In water and are soluble  In
common  organic  solvents  (Hawley,   1981).   The  1986  Directory  of  Chemical
Producers  (SRI, 1986)  reports  that E.I. Dupont  1n Oeepwater,  NJ, currently
produces all three chloroanlUne Isomers; The Upjohn  Co.  1n North Haven, CT,
produces 2-chloroan1l1ne;  First Mississippi  Corp. produces 3-ch1oroan1l1ne;
and Monsanto Co.  1n  Lullng,  LA, produces 4-ch1oroan1l1ne.  Domestic  produc-
tion volume data   for  recent years  could  not be located  1n  the available
literature  as dted 1n Appendix A.  Chloroanlllnes are  used as Intermediates
for azo and azoic  dyes and pigments, pesticides,  rubber  chemicals (2-chloro-
anlllne),  Pharmaceuticals  (3-  and  4-chloroan1l1ne) and agricultural   chemi-
cals  {KouMs  and  Northcott,  1963;  Hawley,  1981; Kuney,  1985).  2-Chloro-
anHlne 1s also used as  a standard  for  colorlmetrlc apparatus  (Hawley,  1981).
    Chloroanlllnes  are  weak  bases  and  as  such, may   be  protonated  under
acidic conditions  and  form salts  that are much  more  water soluble than the
parent  compound.    Protonatlon  may  cause  variations   1n  the  behavior   of
Chloroanlllnes.   If released to the atmosphere,  these compounds  are expected
to  exist  almost  entirely  1n   the  vapor  phase  (E1senre1ch et  al.,   1981).
These compounds should be  removed  from the atmosphere  primarily  by reaction
with photochemlcally generated  hydroxyl  radicals  (estimated half-lives of 3
hours  to  2 days)   (Atkinson,  1985; U.S.  EPA,  1987b)  and possibly by  direct
photolysis  (FreHag et al., 1985).   If released  to water,  chloroanlUnes  are
expected to photooxldlze  on the water  surface  (half-lives estimated  at  0.5
                                      1v

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hours)  (Zepp and  Schlotzhauer,  1983)  and  undergo  rapid  chemical  binding with
humlc  materials  and clay  1n the water column  and In  the  sediment  (Parrls,
1980).  Small amounts of  these  compounds  may  be removed by volatilization or
aerobic  blodegradatlon  by  acclimated microorganisms (Kllzer  et a!.,  1979;
El-Dlb  and  Aly,  1976).   The half-life of 4-chloroanlllne  has  been  estimated
to range  from 0.3-3  days  In rivers  and 30-300 days 1n groundwaters  (Zoeteman
et  al.,  1980).   If  released  to  soil,  chloroanlllnes will  undergo  rapid
chemical  binding  with  soil  components (Bollag et  al.,  1978;  Frletag et al.,
1984)  and be partially removed  by  chemical  and  biological  activity (Bollag
et al.,  1978;  Furukawa and  Brlndley, 1973;  Cloos et al.,  1979).   Volatili-
zation  from soil surface  shoulxl account for  a  loss of  only a  few percent
(Fletcher and Kaufman, 1980).
    Chloroanlllnes may  be released  to the environment  as  fugitive  emissions
or 1n  wastewater  during their production or  use  as  a chemical Intermediate.
Chloroanlllnes may  also form 1n  the  environment  as  degradation  products of
various pesticides  (Bollag  et  al.,   1983; Freltag  et al.,  1984).   The most
probable  routes   of  human  exposure  are  Inhalation  and  dermal • contact  1n
occupational  settings.    2-Chloroan1l1ne  has  been   Identified  In  drinking
water  from  Cincinnati,   OH,  and  Seattle,   WA  (Lucas,  1984).   2-,  3- and
4-Chloroan1l1ne have been  Identified  1n drinking  water  and rivers  1n Germany
(Kussmaul.  1978;  Kool et  al., 1982).   Chloroanlllnes (Isomers  not specified)
have  been detected  1n  the  effluent  from a  publicly owned  treatment  works
(Ellis et al., 1982) and  2-chloroan1line  has  been detected In fish collected
from  a  river near  a sewage treatment plant  (Parrls et al.,  1980).  2- and
4-Chloroan1l1ne have  been Identified as  volatile  flavor components  of  baked
potatoes (Coleman et al., 1981).

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    There  were  three  studies  In  which the  toxlclty  of  all  three chloro-
anHlnes were compared  In the same  test  system,  but these studies  produced
conflicting  results.   Regarding  14-day LC5Qs  for  gupples,  2-chloroan1Hne
was most toxic, followed  by 3-chloroan1l1ne; 4-chloroan1l1ne was least  toxic
(Hermens  et  al.,   1985).   Yoshloka  et  al.  (1985),   however,  found   that
4-chloroan1l1ne  was most  toxic  1n Inhibiting growth of the protozoan Tetra-
hymena   pyrlformls.   followed   by   3-chloroan1l1ne   and  2-chloroan1l1ne.
Devlllers  et al.   (1986)  found  that  4-chloroan1l1ne  was  most  potent  1n
Inhibiting  luminescence  of Photobacterlum  phosphoreum.  followed  by 3- and
2-chloroan1l1ne.  The  lowest  reported  acutely toxic  concentrations were  2
mg/l  4-chloroan1l1ne,  a  96-hour  LC5Q  for bluegllls  (Julln  and  Sanders,
1978);  1.35  mg/l   4-chloroan1l1ne,   a  24-hour  EC™  for  Daphnla  carlnata
(Hattorl et  al.,  1984);  and  0.4  mg/l 4-chloroan1l1ne,  a 96-hour  EC1Q  for
Scenedesmus subsplcatus (Geyer et  al.,  1985).   A 14-day  study by  Hattorl  et
al. (1984)  Indicated  that reproduction of  Daphnla  carlnata was affected  by
0.0427 mg/l 4-chloroan1l1ne but  not by 0.0135 mg/l.
    3-Chloroan1l1ne appears to be  readily absorbed  orally  by  rats;  up  to 75%
of a  single  gavage dose  was  excreted 1n  the urine predominately  as metabo-
lites  within 24  hours   (Boehme  and  Crunow,   1969);  hydroxylatlon  of  the
benzene ring  was  the  primary metabolic alteration.  Jjj. vitro studies  Indi-
cate  that  N-ox1dat1on 1s  the primary  metabolic  route for  4-chloroan1l1ne.
Metabolism studies  of  2-chloroan1l1ne  were  not located,   but  N-ox1dat1on  Is
expected to be the primary mechanism, as 1s  the case with  4-chloroanlllne.
    Pertinent data  regarding  the  effects  of  Inhalation exposure to  the
chloroanlUnes could not  be  located 1n the  available  literature as cited 1n
Appendix A.  Effects of oral administration  of  chloroanlUnes  are  limited to
                                      v1

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4-chloroannine.   In  a  subchronlc  dietary  study  of 4-chloroan1l1ne,  rats
treated at >680  ppm  had  enlarged  spleens  with  plaque formation;  rats treated
at <380 ppm  did  not  (NCI,  1979).   Enlarged spleens  also  occurred In mice fed
at  dietary  levels >11,830 ppm.   At  8080 ppm, all  the mice died  of unknown
causes.  No effects were observed at 5500 ppm.
    Based on an  acute  oral  study using  cats,  4-chloroan1l1ne was  -4  times
more  potent  as  a  methemogloblnemla  Inducer  than were 2-  or  3-chloroan1l1ne
(McLean et al.,  1969).
    4-Chloroan1l1ne  was  administered 1n  the  diet to  rats  at  concentrations
of  250  or 500  ppm and mice  at  concentrations  of  2500  and 5000 ppm  for  78
weeks,  followed  by  observation   periods  of 24  and  13  weeks,  respectively
(NCI, 1979).  Effects  1n the  rats Included reduced  survival In the high-dose
males,  reduced  body  weight gain  In the  high-dose  females, flbrosls  of the
splenic capsule  with  subcapsular mesenchymal  proliferation  In  most  of the
treated males and  females,  and Increased  Incidences  of  splenic  flbromas and
sarcomas  1n  the  high-dose males.   Effects  In  the  mice   Included  markedly
reduced body weight  gain 1n the high- and low-dose  males and females, 1ntra-
cellular deposition  of hemoslderln  1n  many tissues  In  most of  the treated
males  and  females  and  hemanglomatous   tumors   1n   the  treated  males  and
females.  NCI  (1979) concluded that these findings  were   suggestive  of the
cardnogenldty  of 4-chloroan1l1ne  1n  rats and mice.  The  splenic  tumors  In
the rats  were considered  strongly  suggestive  of  cardnogenldty,  however,
because of the  rarity  of these tumors 1n  historical  controls.   Furthermore,
preliminary  results  of  an  NTP gavage  study  using rats  and mice  Indicate  an
Induction  of  splenic  tumors 1n male rats  (Canter, 1985).

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    Specific Information regarding the cardnogenlcUy of 2- or 3-chloroanl-
Une could not be located In the  available  literature as cited  In Appendix A.
Evidence  for  the  N-ox1dat1on  of  monochloroanlUnes  (see Section  5.3)  and
methemoglobln Induction by monochloroanlllnes (McLean et al.,  1969) provides
an  Indication  of  potential  carclnogenlcHy,  however,  as  Induction  of both
carclnogenlcHy  and  methemoblob1nem1a  by  aniline  and  substituted  aniline
compounds  1s  attributed  to the  formation of  N-ox1d1zed  metabolites  (U.S.
EPA, 1984).
    Genotoxoclty  and  cell  transformation  testing  of  2-,  3- and  4-chloro-
anlllne produced positive responses 1n several  assays.  Conflicting results,
a lack  of  corroborating data and, In  the  case  of 2- and 3-chloroan1l1ne, a
                                                 *•
limited variety  of assay types  Indicate  that  evidence  for  genotoxiclty of
the chloroanlllnes should be regarded  as  Inconclusive.
    Specific Information regarding the  teratogenldty  or other reproductive
effects of the  monochloroanlUnes  could  not  be  located 1n  the  available
literature as dted 1n  Appendix  A; however,  the potential for these effects
has been  suggested by the  U.S.  EPA  (1984) on  the  basis  of possible  anoxia
resulting  from  methemogloblnemla  and  reproductive effects produced by other
aniline compounds.
    Given  the  strortg  suggestion  of carclnogenlcHy of 4-chloroanlllne based
on the  Induction of rare splenic  tumors In male rats and  hemanglosarcomas  1n
female and male  mice  (MCI,  1979), and because  preliminary results of  an  NTP
study Indicate that gavage  treatment of rats  also  resulted  In  splenic  tumors
(Canter,  1985),  the   evidence  was   considered  provisionally  limited   and
4-chloroan1l1ne  was  placed  1n  EPA Group C  (although  some  may  consider  It
B2), a possible  human carcinogen.  A  reanalysls of  the  classification  should
be  conducted  after the  new NTP  bloassay  Is  completed  In  1988.   A  q    of

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3.5x10~2  (mg/kg/day)"1  for  oral  exposure  was  derived.    The  concentra-
tions  In drinking water  associated with  Increased  lifetime  risk  of cancer at
risk   levels   of   10~5,   10~»  and  10~7  are   IxlO'2,   IxlCT3   and  lx!0~*
mg/i,  respectively.   An  F   factor  of  4.1xlO~1  (mg/kg/day)"1  was  calcu-
lated,  placing 4-chloroanlllne  In  Potency Group  3.   A Potency  Group  3  and
EPA  Group C  chemical  has  a  low hazard  ranking;  therefore,  the  RQ  based on
cardnogenldty 1s  100.   An  RQ based  on  chronic  tox1c1ty  of 1000  was also
derived based on reduced survival of  rats (NCI,  1979).
    The derivation  of  a  provisional  RfD of 0.01 mg/kg/day  or  0.9 mg/day for
a 70  kg human, which has  been  proposed but not verified (U.S.  EPA, 1986c),
was also presented.   The RfD was  based  on the  LOAEL of  12.5  mg/kg/day (250
ppm) at which  rats  had proUferatlve lesions of the  spleen  (NCI, 1979).   An
uncertainty factor  of  1000  was  used.  Low confidence was placed In  this  RfD
because of  the rare splenic  neoplasms  also observed 1n rats  In this  study.
The final results of  the NTP study may  provide  more  definitive  evidence, as
preliminary results  suggest  that rats  treated by  gavage  developed  spleen
sarcomas  (Canter,   1985).    It   Is  recommended   that   the  provisional  q,*s,
rather than the RfD, be  used  for regulatory  purposes  until  the NTP report Is
available.
    Data were  Insufficient to  derive  any risk  assessment  or RQ values  for
2- and 3-chloroan1l1ne.
                                      1x

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                             TABLE OF CONTENTS
1.  INTRODUCTION	     1

    1.1.   STRUCTURE AND CAS REGISTRY NUMBER	     1
    1.2.   PHYSICAL AND CHEMICAL PROPERTIES 	     2
    1.3.   PRODUCTION DATA	     2
    1.4.   USE DATA	     5
    1.5.   SUMMARY	     5

2.  ENVIRONMENTAL FATE AND TRANSPORT	     6

    2.1.   AIR	     6

           2.1.1.   Reaction with Hydroxyl  Radicals  	     6
           2.1.2.   Reaction with Ozone 	     6
           2.1.3.   Photolysis	     6
           2.1.4.   Physical Removal Processes	     7

    2.2.   WATER	^	     7

           2.2.1.   Hydrolysis	     7
           2.2.2.   Photoox1dat1on	     7
           2.2.3.   M1crob1al Degradation 	     7
           2.2.4.   B1oconcentrat1on	     8
           2.2.5.   Adsorption	    10
           2.2.6.   Volatilization	'	    10
           2.2.7.   Persistence 	    10

    2.3.   SOIL	    11

           2.3.1.   Chemical Degradation	    11
           2.3.2.   M1crob1al Degradation 	    11
           2.3.3.   Adsorption	    12
           2.3.4.   Volatilization	    13
           2.3.5.   Persistence 	    13

    2.4.   SUMMARY	    14

3.  EXPOSURE	    15

    3.1.   WATER	    15
    3.2.   FOOD	    16
    3.3.   INHALATION	    16
    3.4.   DERMAL	    16
    3.5.   SUMMARY	    16

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                          TABLE  OF  CONTENTS (cont.)

                                                                       Page
4.  AQUATIC TOXICITY	   18

    4.1.   ACUTE TOXICITY	   18
    4.2.   CHRONIC EFFECTS	   22
    4.3.   PLANT EFFECTS	   22
    4.4.   SUMHARY	   22

5.  PHARMACOKINETCS	   26

    5.1.   ABSORPTION	   26
    5.2.   DISTRIBUTION	   26
    5.3.   METABOLISM	   26
    5.4.   EXCRETION	   27
    5.5.   SUMMARY	   28

6.  EFFECTS	   29

    6.1.   SYSTEMIC TOXICITY.	'.....	   29

           6.1.1.   Inhalation Exposures	   29
           6.1.2.   Oral Exposures	   29
           6.1.3.   Other Relevant Information	   31

    6.2.   CARCINOGENICITY	•	   32

           6.2.1.   Inhalation	'.	   32
           6.2.2.   Oral	   32
           6.2.3.   Other Relevant Information	   37

    6.3.   MUTAGENICITY	   37
    6.4.   TERATOGENICITY	   45
    6.5.   OTHER REPRODUCTIVE EFFECTS 	   45
    6.6.   SUMMARY	   45

7.  EXISTING GUIDELINES AND STANDARDS 	   48

    7.1.   HUMAN	   48
    7.2.   AQUATIC	   48

8.  RISK ASSESSMENT	   49

    8.1.   CARCINOGENICITY	   49

           8.1.1.   Inhalation	   49
           8.1.2.   Oral	   49
           8.1.3.   Other Routes	   51
           8.1.4.   Weight of Evidence	   51
           8.1.5.   Quantitative Risk Estimates  	   51
                                     x1

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                           TABLE  OF  CONTENTS (cont.)

                                                                        Page

     8.2.   SYSTEMIC TOXICITY	   53

            8.2.1.   Inhalation Exposure 	   53
            8.2.2.   Oral Exposure	   53

 9.  REPORTABLE QUANTITIES 	   55

     9.1.   BASED ON SYSTEMIC TOXICITY 	   55
     9.2.   BASED ON CARCINOGENICITY	   57

10.  REFERENCES	   63

APPENDIX A: LITERATURE SEARCHED	   85
APPENDIX B: CANCER DATA SHEET FOR DERIVATION OF q-.*s	   88
APPENDIX C: SUMMARY TABLE FOR 4-CHLOROANILINE	   90

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No.
1-1
1-2
4-1
4-2
4-3

6-1

6-2

6-3

6-4

9-1

9-2
9-3

9-4

9-5
LIST OF TABLES
Title
Selected Physical Properties of ChloroanlUnes 	
Current Manufacturers of ChloroanHlnes 	
Acute Toxlclty of ChloroanlUnes to Freshwater Fishes ....
Acute Toxlclty of ChloroanlUnes to Invertebrates 	
Toxlclty of ChloroanlUnes to Freshwater Plants and
Bacteria 	
Incidences of Tumors 1n F344 Rats and B6C3F1 Mice Treated
with Technical Grade 4-Chloroan1l1ne 1n the Diet 	
MutagenlcHy and Other Short-Term Assays of
2-Chloroan1l1ne 	
MutagenlcHy and Other Short-Term Assays,of
3-Chloroan1l1ne 	 * 	
MutagenlcHy and Other Short-Term Assays of
4-Chloroan1l1ne 	
Oral Toxlclty Summary for 4-Chloroan1l1ne (technical
grade) 1n Diet 	
Oral Composite Scores for 4-Chloroan1l1ne Using the Rat . . .
4-Chloroan1l1ne: Minimum Effective Dose (MED) and
Reportable Quantity (RQ) 	
2- and 3-Chloroan1l1ne: Minimum Effective Dose (MEO) and
Reportable Quantity (RQ) 	
Derivation of Potency Factor (F) for 4-Chloroan1l1ne 	

Page
3
4
19
21

23

34

38

40

41

56
58

59

60
61

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                             LIST  OF  ABBREVIATIONS
BCF                     Bloconcentratlon factor
BUN                     Blood urea nitrogen
CS                      Composite score
ONA                     Deoxyrlbonuclelc acid
ECso                    Concentration effective to 50% of recipients
Koc                     Soil sorptlon coefficient standardized
                        with respect to soil organic matter
Kow                     Octanol/water partition coefficient
LCg                     Concentration lethal to 0% of recipients
LCso                    Concentration lethal to 50% of recipients
LOAEL                   Lowest-observed-adverse-effect level
MED            .         Minimum effective dose
NOAEL                   No-observed-adverse-effect level
NOEC                    No-observed-effect concentration
ppb                     Parts per billion
ppm                     Parts per million
RfO                     Reference dose
RQ                      Reportable quantity
RV,j                     Dose-rating value
RVe                     Effect-rating value
UV                      Ultraviolet
                                      x1v

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                               1.  INTRODUCTION
 1.1.   STRUCTURE AND CAS REGISTRY NUMBER
    The  synonyms,  structure  and CAS  Registry  number  for  2-,  3- and 4-chloro-
 an111ne  are as follows:
 2-Chloroanlllne
 CAS Registry number:  95-51-2
 Synonyms:    ortho-Chloroan1l1ne;   l-am1no-2-chlorobenzene;   2-chlorophenyl-
 amlne;  2-chlorobenzenam1ne;  Azoic Dlazo  Component  44;  CI 37000  (KouMs  and
 Northcott, 1963); Fast Yellow GC Base (U.S. EPA, 1987a):
 Structure:
3-Chloroan1l1ne
CAS Registry number:  108-42-9
Synonyms:   meta-Chloroan111ne;  l-amlno-3-chlorobenzene;  3-chlorophenylam1ne;
3-chlorobenzenam1ne;  Azoic   Dlazo  Component   2;   CI  37005   (Kourls   and
Northcott. 1963); Fast Orange GC Base (U.S. EPA. 1987a)
Structure:
4-Chloroan1l1ne
CAS Registry number:  106-47-8
Synonyms:  para-chloroanlllne;  l-am1no-4-chlorobenzene;  4-chloropheny1am1ne;
4-ch1orobenzenam1ne (U.S. EPA, 1987a).
0028d
-1-
05/15/87

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Structure:
                  Cl
Each of  the chloroanlUne Isomers has a  molecular  weight  of 127.58 and the
empirical formula C^H^CIM.
1.2.   PHYSICAL AND CHEMICAL  PROPERTIES
    2-Chloroan1l1ne  1s  an amber  liquid;  3-chloroan1l1ne Is  a  colorless to
light amber  liquid;  and 4-chloroan111ne  1s a  white  to  pale yellow solid at
room temperature (Hawley, 1981).  Aromatic amines are oxidized easily by air
                                                 ^
and chloroanllines  have  a tendency to darken  on  exposure  to air because of
the formation of oxidation products (Hawley. 1981; Morrison and Boyd, 1973).
Aromatic amines  are weak bases and may  be  readily  converted to their  salts
by  aqueous  mineral  adds or  carboxyllc  adds.   Aqueous  hydroxyllons can
readily  convert  these  salts  back  to the  free  amlne   (Morrison  and  Boyd,
1973).   Chloroanlllnes are soluble  1n most  common organic  solvents  {Hawley,
1981; Hlndholz,  1983).   Selected physical  properties  for  the  ch1oroan1!1ne
Isomers are listed In Table 1-1.
1.3.   PRODUCTION DATA
    Halogenated  anilines such  as  chloroanlUnes  are   usually  produced by
reduction of the corresponding nltro compounds  1n  the  presence of  Iron and
hydrochloric add.   Chloroanlllnes  may also  be  made by the ammonolysls of
the  appropriate  bromochlorobenzene  (Kourls   and   Northcott,   1963).    Data
regarding  current   domestic  manfacturers  of   Chloroanlllnes  are  listed  In
Table  1-2.   Domestic  production  volume  data could  not be  located 1n the
available literature as cited  In Appendix A.   The most  recent year  for  which


0028d                               -2-                              06/05/87

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0028d
-3-
05/15/87

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                                  TABLE 1-2

                   Current Manufacturers  of  ChloroanlUnes*
   Chemical
      Manufacturer
   Location
2-Chloroan1l1ne


3-Chloroan111ne


4-Chloroan1l1ne
E.I. Dupont
The Upjohn Co.

E.I. Dupont
First Mississippi Corp.

E.I. Oupont
Monsanto Co.
Deepwater, NJ
North Haven, CT

Oeepwater, NJ
Pascagoula, MI

Deepwater, NJ
Lullng, LA
*Source: SRI, 1986
0028d
         -4-
       05/15/87

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 Import  data  are available 1s 1983, during which  179,649  pounds  of  2-chloro-
 anlUne  and  830,915  pounds  of  3-chloroan1l1ne  were  Imported  through  the
 principle U.S. customs districts (USITC, 1984).
 1.4.   USE DATA
    ChloroanlUnes  are  used  as  Intermediates for  azo and  azoic  dyes  and
 pigments,  pesticides,  rubber  chemicals  (2-chloroan1l1ne),   Pharmaceuticals
 (3- and  4-chloroan1l1ne)  and agricultural  chemicals  (Society  of  Dyers  and
 Colorlsts,  1971;  Kourls  and Northcott,  1963;  Hawley,  1981;  Kuney,  1985).
 2-Chloroan1l1ne  1s  also  used   as  a   standard  for  colorlmetMc   apparatus
 (Hawley, 1981).
 1.5.   SUMMARY
                                                *»
    2-Chloroan1l1ne (CAS  number  95-51-2)  1s  an amber liquid;  3-chloroan1l1ne
 (CAS  number  108-42-9) 1s  a  colorless  to  light  amber liquid; and  4-chloro-
 anlUne  (CAS  number  106-47-8)   1s  a  white  to   pale  yellow  solid  at  room
 temperature  (Hawley,  1981).  They are  slightly   soluble  1n  water  and  are
 soluble  1n  common organic  solvents  (Hawley, 1981).   The 1986  Directory  of
 Chemical Producers  (SRI,  1986)   reports  that E.I.  Dupont 1n  Deepwater,  NJ,
 currently produces all  three chloroanHlne  Isomers; The Upjohn  Co.  1n  North
 Haven,  CT,   produces   2-chloroan1l1ne;   First  Mississippi   Corp.   produces
 3-chloroan1l1ne; and  Monsanto Co.  In  Lullng, LA,  produces  4-chloroan1l1ne.
 Domestic production volume data  for recent years  could not be located  1n the
available  literature  as  cited   In  Appendix  A.    ChloroanlUnes  are used  as
 Intermediates  for  azo   and   azoic  dyes  and  pigments,  pesticides,  rubber
chemicals  (2-chloroan1l1ne), Pharmaceuticals  (3-  and  4-chloroan1l1ne)  and
agricultural  chemicals  (Kourls  and Northcott,  1963;  Hawley,   1981;  Kuney,
1985).   2-Chloroan1l1ne  1s  also  used  as  a   standard for  colorlmetrlc
apparatus (Hawley, 1981).


0028d                               -5-                              06/05/87

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                     2.   ENVIRONMENTAL  FATE  AND TRANSPORT

    ChloroanHlnes are  weak  bases [pKa 2.66-3.98  (PerMn,  1972)]  which may
be protonated under addle conditions to form salts that are much more water
soluble than  the  parent compound.  Protonatlon can alter  the  behavior of a
compound  In  water and  soil,  for  example,  by decreasing  volatilization as
well as decreasing or  Increasing  physical  adsorption  to soil,  sediments and
suspended solids 1n water.
2.1.   AIR
    Based on the vapor pressures  listed In  Table 1-1, the  chloroanlllnes are
expected  to  exist  almost entirely  1n  the vapor  phase   1n  the atmosphere
(Elsenrelch et al., 1981).
2.1.1.    Reaction with  Hydroxyl   Radicals.   Using  experimentally determined
hydroxyl  reaction rate  constants  of   8.30x10'"  cmVmolecule-sec  at  22°C
(Atkinson, 1985)  and  8.09x10""  cmVmolecule-sec  at  27*C  (Gusten  et  al.,
1984)  and  an  ambient  hydroxyl   radical   concentration   of   8.0x10*   mole-
cules/cm3  (U.S.  EPA,  1987b),   the   half-life  for  4-chloroan1l1ne   vapor
reacting  with  photochemlcally  generated hyroxyl  radicals  In  the atmosphere
has been  estimated to  be  ~3  hours.  The half-lives for 2-,  3- and  4-chloro-
anHlne vapor reacting with photochemlcally generated hydroxyl radicals  have
been estimated  to be  -2 days  based on  an estimated  reaction  constant  of
5.1xlO~12 cmVmolecule-sec at  25°C (U.S. EPA, 1987b).
2.1.2.    Reaction with Ozone.  Chloroanlllnes  are  not  susceptible to  oxida-
tion by ozone 1n the atmosphere (U.S. EPA,  1987b).
2.1.3.    Photolysis.    4-Chloroan1l1ne   adsorbed  onto  silica  gel   underwent
27.7% mineralization when  Irradiated with  light  of wavelengths  >290  nm for
17 hours  (Freltag  et  al.,  1985).   Chloroanlllnes  In methanol  or cyclohexane


0028d                               -6-                              05/15/87

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 strongly  absorb  UV  light  1n  the environmentally  significant  wavelength  range
 of  >290  nm  (Sadtler  Research  Laboratory,  1960a,b,   1962).    These   data
 Indicate  that chloroanlUnes  have  the  potential  to  undergo  direct photolysis
 In the atmosphere.
 2.1.4.    Physical  Removal  Processes.   Based  on  the  water   solubilities
 listed  In Table  1-1,  It appears that  small  amounts of  chloroanlUnes may  be
 removed from the atmosphere 1n wet precipitation.
 2.2.   WATER
 2.2.1.    Hydrolysis.    Halogenated  aromatlcs   and   aromatic   amines   are
 generally resistant to  hydrolysis  (Lyman et  al.,  1982);  thus,  chloroanlUnes
 are expected to be resistant to hydrolysis.
 2.2.2.    Photoox1dat1on.   The   sunlight-Induced"  photolysis  half-life   of
 4-chloroan1l1ne  In distilled water has been  estimated to be  -0.5 hours  using
 an  experimentally determined  reaction  rate constant  of   1.76   hr"1.   This
 rate  was  not  significantly Increased  by  the presence of algae  1n  the  water
 (Zepp and Schlotzhauer, 1983).   No  transformations  1n  4-chloroan1l1ne  were
 observed  when aqueous  solutions of  this  compound  were  kept In  the  dark  for
 3-4  hours (Zepp  and  Schlotzhauer,  1983).   Irradiation of  10"*  M  4-chloro-
 anlllne In air-saturated water with  UV light  of  wavelengths  >290 nm produced
 4-chloronltrosobenzene  and 4-chloronltrobenzene;  4-chloroan1l1ne would  not
 be detected after 6  hours  of Irradiation  (Miller and Crosby,  1983).  2- and
 3-Chloroan1l1ne   exposed to UV  light  of  wavelengths  >300  nm underwent  50%
 degradation after 7.5 and 11.5 minutes, respectively (Kondo,  1978).
 2.2.3.   M1crob1al  Degradation.    The  results  of  blodegradatlon  screening
 studies  on chloroanlUnes  range from no degradation or  m1crob1al Inhibition
 to  rapid   degradation   using   freshwater,  activated  sludge  and  sewage  as
 Inocula  (GeMke  and  Fischer,  1981;  Kawasaki,  1980;  King and  Painter.  1983;


0028d                               -7-                              05/15/87

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Janlcke and H1lge,  1980;  El-D1b  and  Aly,  1976; Malaney, 1960; Thorn and Agg,
1975; Balrd et  al.,  1977;  PHter,  1976;  Schmldt-Bleek et al., 1982; FreHag
et al.,  1985).   The most frequently reported  results  Indicate  that chloro-
anlUnes degrade slowly with acclimation  (Thorn and  Agg, 1975; Balrd et al.,
1977; PUter,  1976;  Schmldt-Bleek  et  al.,  1982;  Halaney,  1960;  El-01b and
Aly,  1976).   In one river  die-away  study,  10  ppm  4-chloroan1l1ne degraded
slowly  1n  Nile  River water over a  period of  2 months;  on  redose, however,
Increasingly  larger  concentrations  were  degraded over  a diminishing period
of time.  On  the eighth redose, 100 ppm 4-chloroanlllne was degraded In just
a  few days  (El-D1b and Aly, 1976).  A proposed pathway for  the blodegrada-
tlon of 2-chloroan1l1ne 1s  shown 1n  Figure  2-1.^  The first Intermediates 1n
the metabolism  of  chloroanlUnes by £_._ multlvorans  strain An.l  were chloro-
catechols (Reber et  al.,  1979).   Pseudomonas aurantlaca converted  4-chloro-
anlllne  to  Us  corresponding  acetanlUde  (Surovtseva  et  al.,  1977).  No
mineralization  of  4-chloroan1l1ne  occurred  when this compound was  Incubated
with  digester  sludge under  anaerobic  conditions  for  1 month  (Shelton and
Tledje,  1981).
2.2.4.   Blconcentratlon.   BCF  values  of  13-20 1n  the  In  the  Golden  orfe,
Leudsens Idus  melanotus. and  260-1200 In algae,  Chlorella  fusca.  have been
measured  for  4-chloroan1l1ne  (Korte  et   al.,   1978;  FreHag  et  al.,   1985;
Geyer et  al.,  1984).   Based  on the  log K    values  listed In  Table 1-1,
B'CFs of 16, 16  and 14 were  estimated for  2-,  3- and 4-chloroan1l1ne, respec-
tively,  using the  following recommended linear  regression equation  (Lyman et
al., 1982):   log  BCF « 0.76 log K   - 0.23.   These BCF values suggest  that
bloaccumulatlon of chloroanlUnes 1n aquatic organisms  would  not  be signifi-
cant.
0028d                               -8-                              06/05/87

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  HOOC
       COOH ci
COOH
                      COOH
 HOOC
         COOH
     CH3COOH  +
 *HOOC-CH=CH-COOH
                        FIGURE 2-1
          Proposed B1odegradat1on Pathway of 2-Ch1oroan1"Mne
                     Source:  Rump, 1984
0028d
-9-
                       05/15/87

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2.2.5.   Adsorption.   2-Chloroan1l1ne   and   4-chloroan1l1ne  have  been  ob-
served undergoing rapid, reversible covalent binding with humates In aqueous
solution.  This  reaction 1s  believed  to represent  the  formation  of  1m1ne
linkages  with  humate  carbonyl   groups.   This  Initial  binding  reaction Is
followed by  a  much  slower,  less  readily  reversible  binding reaction,  which
Is believed  to represent  the  addition  of  the amines to qulnoldal structures
followed by  oxidation  of  the  product  to a nitrogen substituted  qulnold  ring
(ParMs,  1980).   The  model  half-life  of 4-chloroanHlne  binding  with one
test  humlc  constituent,  p-benzoqu1none,  was  13  minutes  (ParMs,   1980).
Based on these observations, 1t  Is expected  that  chemical  binding of chloro-
anlUnes  to  humlc  substances present  In  sedlmepts and  suspended  solids 1n
water would be significant.
2.2.6.   Volatilization.   Under  laboratory   conditions,   50  ppb   4-chloro-
anlUne 1n aqueous solution underwent 0.63%  loss, which was  due  to  volatili-
zation after  2 hours  (Kllzer  et al.,  1979).   Henry's  Law  constants  calcu-
lated from vapor pressure and  water  solubility data listed  1n Table 1-1 are
7.5xlO~*  atm-mVmol   at   20°C   for   3-chloroan1l1ne,  1.7xlO~* atm-mVmol
at   20°C   for  3-chloroan1l1ne   and   1.2xlO~*   atm-mVmol   at   -25°C  for
4-chloroan1l1ne.   Based on these  values,  the volatilization  half-life  from  a
typical  river  1 m  deep,  flowing 1  m/sec with  a wind  speed of  3 m/sec has
been  estimated  to be  5.5,  24  and  34 days  for  2-, 3- and  4-chloroanlllne,
respectively, using the method of Lyman et al. (1982).
2.2.7.   Persistence.   The  half-life  of  4-chloroan1l1ne  has been  estimated
to  range  from 0.3-3  days 1n  rivers  and  from 30-300  days 1n  groundwaters
(Zoeteman  et al.,   1980).   When  4-chloroan1l1ne  with  trace amounts   of  the
14C-labeled  material was  applied to experimental  ponds for 4-6 weeks at  an
average  concentration   of  -50   yg/l,   14C   disappeared   from  the  water  1n


0028d                               -10-                             06/05/87

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 two  phases  with  half-lives  of ~3 and  11  days,  respectively.   It  was assumed
 that  Initial  loss  was  the result of volatilization.   After  3 days,  products
 of  autooxldatlon,  with lower  volatility,  caused a  decrease 1n  the  rate  of
 14C  loss from  water.   No  significant  leaching  horizontally  or  vertically
 Into  the soil  surrounding  the  experimental  pond  was  observed.  One  year
 after  application,  -10-20X  of  the  total  14C  applied  was  present  as  bound
 residues 1n the upper  0-  to  10-cm  soil layer (Schauerte et  al., 1982).   In 2
 weeks,  250  vq/l  3- and  4-chloroan1l1ne  added to  separate eutrophlc  pond
 water  samples underwent 7 and  4X removal,  respectively.   In  a similar study,
 3- and  4-chloroan1l1ne added  to  eutrophlc  pond water  samples  with  sewage
 sludge  Inoculum underwent  9  and  7% removal,  respectively, In 2 weeks (Lyons
                                                 *•
 et  al.,  1985).   At   30°C,  0.1  wl/mi  3-chloroanlllne   Incubated  1n  three
 different river  water  samples In  the  dark had  a half-life  of 3-7  days.
 Under  the  same test  conditions  using two  different  samples of  sea  water,
 this compound had a half-life of  -3 days (Kondo, 1978).
 2.3.   SOIL
 2.3.1.   Chemical   Degradation.    Pertinent   data  regarding   the   chemical
 degradation of  chloroanHlnes  In   soil  other  than  those given   1n  Section
 2.3.3.  could  not  be   located  1n   the  available  literature  as  cited  1n
 Appendix A.
 2.3.2.   M1crob1al  Degradation.    In   autoclaved  and   nonautoclaved   soil
 treated  with  5  ppm  [l4C]-4-chloroanH1ne  and Incubated  for  6 weeks,  no
 14C02   evolution   was   observed    1n   the   autoclaved   sample,  but   7.5X
 14C02  was   released  from  the  nonautoclaved  soil   (Bollag   et   al.,  1978).
Alexander and Lustlgman  (1966)  found  10  yg/l  2-,   3-  and  4-chloroan1l1ne
 Inoculated  with  mixed   cultures  of  soil  microorganisms  to  be  resistant  to
degradation.   A   Pseudomonas   species  Isolated  from  soil   and  grown  under


0028d                               -11-                             05/15/87

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aerobic conditions used 4-chloroanlUne as a sole source of C and M.  A mass
balance  on  [l*C]-4-chloroanH1ne  revealed  that 64%  of  **C  was  released
as  CO-  and 14% was  associated  with the  blomass  (Zeyer  and Kearney,  1982).
Fusarlum  oxysporum  Schlecht  Isolated  from  soil-degraded  4-chloroan1l1ne
through at  least  two metabolic pathways.  Oxidation of  the amlne group was
the  primary  mechanism,  but  acylatlon  of  the  amlne  group  also  occurred
(Kaufman et  al.,  1973).   A  Paracoccus  species  Isolated  from soil and grown
under  anaerobic  conditions  metabolized  4-chloroan1l1ne  Into  a   product
Identified as 1,3-b1s(p-chlorophenyl)tr1azene (Mlnard et  al., 1977).
2.3.3.   Adsorption.    The  K    of  4-chloroan1l1ne  has  been  determined   to
range  from 96-1530  In a  variety of  soils.   Lower  soil  pHs  produced lower
K    values Indicating the   Importance  of covalent  binding to  soils   (Van
Blade!  and Horeale,   1977;   Rlppen  et  al.,  1982).   After  Incubating 5 ppm
[l4C]-4-chloroan1!1ne  In  autoclaved  and  nonautoclaved  soil  (3.4%  organic
matter)  for  6  weeks,  71.0  and 72.4%,  respectively,  of  total  14C  applied
was  found  to  exist as soil-bound  residues (Bo"Mag  et  al., 1978).  Based  on
the  results  of  a   3-year  field  lyslmeter   study,  Freltag  et  al.   (1984)
speculated  that  rapid  binding  Immobilizes 4-chloroan1l1ne  1n  soil and  only
very  small  amounts of  free  chloroanlllne are able to  leach Into  deeper  soil
layers.    Bartha   (1971)  determined   that  Immobilized   chloroanlUnes  are
chemically bound  to  humlc  substances  and physical adsorption Is,  at  most, a
secondary  process.   Studies  by  other   Investigators also  Indicate that  the
chloroanlllne  should  undergo rapid, tight binding  with humlc  substances  1n
soil  (Worobey  and  Webster, 1982;  Bollag  et  al.,  1983;  ParMs,   1980).
Adsorption  and  oxidation  of aromatic  amines  can occur  on  clay  surfaces  but
1s  dependent  on  the exchangeable cation  In  the  clay  and  the  presence  of
oxygen  (Furukawa  and BMndley,  1973;  Cloos  et  al.,  1979), as  Indicated  by
0028d                               -12-                             06/05/87

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the  formation  of  olIgomeMc  and polymeric complexes when 4-chloroan1l1ne  1s
adsorbed  onto  montmorlllonlte  clay  (Cloos  et  al.,  1979).   The  K    value
for  4-chloroan1l1ne  adsorbed  onto   colloidal   organic   matter  present   1n
groundwater samples was  found  to  be  5550 (Means, 1983),  which suggests that
adsorption onto  this  mlcropartlculate  matter could effectively  Increase  the
solubility and leaching of chloroanlUnes Into landfill  groundwater.
2.3.4.   Volatilization.   Under   laboratory   conditions,   4-chloroan1l1ne
applied to sand, loam and  humus underwent 2.01,  0.72 and  0.11% loss,  respec-
tively, 1n  2  hours, which was  due  to  volatilization (KHzer et al.,  1979).
After  49  days,  <2% of  3-chloroan1l1ne applied  to unsteMUzed  Hagerstown
sllty clay loam was found to have volatilized  (Hetcher  and Kaufman,  1980).
Based on the strong binding  of  chloroanlllnes to  soil organic matter  and  the
partial protonatlon of  these  compounds In  acidic soils  (see  pKa  values
listed  1n  Table  1-1),  volatilization from wet  and  dry  soil surfaces  1s  not
expected to be significant.
2.3.5.   Persistence.    When   50  mg  [l4C]-4-chloroan1Hne,   which   corre-
sponded to  1.25 ppm  1n  soil  to  a  depth of  10 cm, was added to  a  field
lyslmeter,  a   total  of  32.8%  of  the  14C   applied  was  recovered  20  weeks
later:  32.4%  1n  soil,  0.3% 1n plants  and  0.1% In  leached  water.   Of  the
total  4-chloroan1l1ne  present  1n the  soil,   >90% was  1n the  form of  soil-
bound  residues  (Freltag   et  al.,  1984).    A  16-week   study  of  2-,  3-  and
4-chloroan1l1ne  1n  two   different   soils    revealed   that   3-chloroanlHne
degradation (10.6-11.9%)  was  the  fastest of   the  three  Isomers  (Fuchsblchler
et al., 1978).   During a  16-week study  of this  compound  1n  four  agricultural
soils,  12.3-17.2%  mineralization  of  4-chloroan1l1ne was  observed  (Suess  et
al.,  1978).
0028d                               -13-                             06/05/87

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2.4.   SUMMARY
    Chloroan111nes  are  weak  bases  and  as  such,  may  be  protonated  under
acidic conditions  and  form salts  that are  much  more water soluble than the
parent  compound.    Protonatlon   may  cause  variations  In  the  behavior  of
chloroanlUnes.  If released to  the  atmosphere, these compounds  are expected
to  exist almost  entirely  1n  the  vapor  phase  (E1senre1ch et  al.,   1981).
These compounds should be  removed  from the atmosphere primarily by reaction
with photochemically generated  hydroxyl  radicals  (estimated half-lives of 3
hours to  2  days)  (Atkinson,  1985; U.S.  EPA.  1987b)  and  possibly by  direct
photolysis (FreHag et al., 1985).   If released to water,  chloroanlUnes are
expected  to  photooxldlze  on the water surface (-half-lives estimated  at 0.5
hours) (Zepp and Schlotzhauer, 1983) and undergo rapid chemical  binding with
humlc materials  and clay  1n  the water column and  1n the  sediment (Parrls,
19.80).  Small amounts of these compounds may be removed by volatilization or
aerobic   blodegradatlon  by  acclimated  microorganisms (Kllzer  et al., 1979;
El-01b and Aly,  1976).   The half-life  of 4-chloroan1l1ne  has  been  estimated
to range  from 0.3-3 days 1n rivers  and 30-300  days  In groundwaters  (Zoeteman
et  al.,   1980).   If  released  to  soil,   chloroanlUnes  will  undergo rapid
chemical   binding with soil  components  (Bollag  et al., 1978; Frletag et al.,
1984) and be  partially  removed  by  chemical  and  biological activity  (Bollag
et al.,   1978;  Furukawa  and BMndley,  1973;  Cloos  et al.,  1979).   Volatili-
zation from  soil  surface  should account for  a  loss of  only  a  few  percent
(Fletcher and Kaufman,  1980).
0028d                               -14-                             06/05/87

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                                 3.  EXPOSURE

    The  National   Occupational   Hazard   Survey   (NOHS)   prepared  by  NIOSH
estimates  that  18,138 workers are occupatlonally  exposed  to 2-chloroan1l1ne
(NIOSH, 1984).  NOHS  estimates were  not  provided  for  the other chloroanHlne
Isomers.   The most  probable  routes  of  human  exposure  are  Inhalation  and
dermal contact In occupational settings.
    Chloroanlllnes  may  be released to the environment as  fugitive emissions
or  1n  wastewater  during  their production or use  as  chemical  Intermediates.
Chloroanlllnes may  also form  1n  the  environment  as  degradation  products  of
various pesticides  (Bollag et al., 1983; Fre1tag,et a!.,  1984;  Suess, 1973).
3.1.   WATER
    2-Chloroan1l1ne has  been  positively  Identified 1n drinking water samples
obtained  from Cincinnati,  OH,  In  1980  and Seattle,  HA,  1n 1976  (Lucas,
1984).  The  mean  concentration  of  4-chloroan1l1ne In German  drinking  water
(treated  Rhine  water)   from  September 1973  to  September   1974  was 7  ng/l
(Kussmaul,  1978).    2- and   3-Chloroan1l1ne  have  also  been  detected  In
drinking water In Germany (Kool et al., 1982).
    During 1979, the mean concentration of 2-,  3- and 4-chloroan1l1ne 1n the
Rhine  River  at LobUh  was  0.52,  0.14 and  0.22   yg/l,  respectively (Wegman
and  Oekorte,  1981).    During  1979,   the  mean  concentration  of   2-,  3- and
4-chloroan1l1ne  1n   the  Meuse  River  at  Eljsden  was  0.86,  0.06 and  0.08
jig/1,  respectively,  and  at  L1th,   0.06,   0.02   and   0.01  jig/l,  respec-
tively  (Wegman  and Dekorte,  1981).    4-Chloroan1l1ne  was  detected 1n  the
Rhine River from September 1973  to September  1974 at a mean concentration of
100  ng/l   (Kussmaul,   1978).   2-,   3- and   4-Chloroan1l1ne  have  also  been
found 1n the delta waters from the Rhine River (Greve and Wegman,  1975).


0028d                               -15-                             06/05/87

-------
    Chloroanlllnes  (Isomers  not  specified)  have  been   detected   In   the
effluent from the publicly owned treatment works  (POTW)  of  Sauget,  IL (Ellis
et  al.,  1982).   In Adrian,  MI, 600  ppm (dry weight basis)  2-chloroan1l1ne
was  found  1n  the  sediment   of  a   waste   treatment   lagoon   of   a  small
4,4'-methyleneb1s(2-chloroan1l1ne)   manufacturer.    This   compound  has  also
been   detected  In fish  collected  from a river near  the Adrian, MI,  sewage
treatment plant (Parrls et al.,  1980).
    Since 4-chloroan1l1ne  readily  adsorbs  onto colloidal organic matter  and
adsorption   onto   m1cropart1culates>   could   effectively   Increase   the
leachabllHy of  the  chloroanlllnes from landfills  Into  groundwater,  ground-
water 1s theoretically a potentially significant  source  of human exposure.
3.2.   FOOD
    2- and  4-Chloroan1l1ne  have been  Identified  as  volatile  flavor  compo-
nents of Idaho Russet  Burbank baked potatoes  (Coleman et  al.,  1981).
3.3.   INHALATION
    Pertinent data regarding exposure  by Inhalation could  not  be  located  In
the available literature as cited 1n Appendix A.
3.4.   DERMAL
    Pertinent data regarding exposure  by dermal contact  could not be located
In the available literature as  cited in Appendix  A.
3.5.   SUMMARY
    Chloroanlllnes may  be released to the environment as  fugitive  emissions
or 1n wastewater  during their  production or use  as  a  chemical  Intermediate.
Chloroanlllnes may also form 1n the  environment  as degradation  products  of
various  pesticides  (Bollag et  al.,  1983;  Freltag  et  al., 1984).   The most
probable  routes  of  human  exposure  are Inhalation  and  dermal  contact  In
occupational  settings.   2-Chloroan1l1ne  has  been  Identified  1n  drinking


0028d                               -16-                             07/21/87

-------
water  from  Cincinnati,   OH,  and  Seattle,  HA  (Lucas,   1984).   2-,  3- and
4-Ch1oroan1l1ne  have been  Identified  In  German  drinking  water and  German
rivers  (Kussmaul,   1978;  Kool  et  al.,  1982).   ChloroanHlnes  (Isomers  not
specified)  have  been detected  In  the effluent from a publicly  owned  treat-
ment  works (Ellis  et  al.,  1982)  and  2-chloroan111ne  has  been  detected  In
fish  collected  from a  river  near a  sewage  treatment  plant  (Parrls et  al.,
1980).   2- and  4-Chloroan111ne  have  been   Identified   as  volatile  flavor
components of baked potatoes (Coleman et al., 1981).
0028d                               -17-                             07/21/87

-------
                             4.   AQUATIC TOXICITY
4.1.   ACUTE
    The available data concerning acute  toxldty of  chloroanlllnes  to  fresh-
water fishes are  presented  1n  Table 4-1.  The only  study 1n which  all  three
chloroanlllnes were tested was that of  Hermens et  al.  (1985)  1n  which  14-day
LC5Q  values  for  gupples, Poec111a  retlculata.  were determined.   These  data
suggested  that 2-chloroan1l1ne  was  the  most  toxic   (LC5Q  =  6.25  mg/l),
3-chloroan1l1ne was   Intermediate  (LC5Q =  13.36   mg/l)  and  4-chloroanlllne
was  the  least toxic {LC50  -  26.05  mg/l).   The  most  sensitive  species
tested  appeared  to  be  the  blueglll,  Lepomls  macrochlrus. with  a  96-hour
LC5Q  of  2  mg/l   4-chloroan1l1ne   (Julln  and  Sanders,  1978),   the  lowest
reported acutely  toxic  concentration  for freshwater fishes.   Data  regarding
marine  fish  species  could  not  be located  1n  the  available literature  as
cited In Appendix  A.
    ChloroanHlne   acute  toxldty  data  for  Invertebrates  are  presented  In
Table 4-2.   The only  one of these  studies  1n which  all  three chloroanlllnes
were compared was that of Yoshloka  et al.  (1985).   These Investigators found
that  4-chloroan1l1ne  was much more  toxic  than  3-chloroan1l1ne  or  2-chloro-
anlUne to  the dilate  protozoan,  Tetrahymena  pyrlformls.   EC,Q  values for
growth  Inhibition  1n this  study  were  10 mg/l  for  4-chloroanlllne,  100
mg/l  for   3-chloroan1l1ne  and  200  mg/l  for   2-chloroan1l1ne.   The  lowest
reported  toxic concentration  for  freshwater  Invertebrates  was   1.35  mg/l
4-chloroan1l1ne,   a   24-hour   EC5Q   for   the   cladoceran   Daphnla  carlnata
(Hattorl et  al.,   1984).   For saltwater  Invertebrates, the  lowest reported
toxic concentration  was  10  mg/l  4-chloroan1l1ne  which  Impaired development
of oyster, Crassostrea v1rq1n1ca embryos (EG&G,  1979).
0028d                               -18-                             05/15/87

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4.2.   CHRONIC EFFECTS
    The  only  chronic  toxldty  data  for  chloroanlUnes  were  provided  by
HattoM et al. (1984) who reported that reproduction of Daphnla  caMnata was
affected by  4-chloroanlllne  concentrations  as  low as  0.0427  mg/l 1n 14-day
exposures.   Only the abstract  of  this  Japanese paper was translated, and no
other details were provided.   A  figure In  the paper seemed to Indicate that
reproduction was not  significantly  affected  by 4-chloroanlllne at a concen-
tration of 0.0135 mg/l.
4.3.   PLANT EFFECTS
    The  available  Information  concerning  effects   of  chloroanlUnes  on
aquatic plants and bacteria  Is presented  1n Tabje 4-3.  The  lowest  reported
toxic  concentration   was  0.4  mg/l  4-chloroan1l1ne,  which  was  a  96-hour
EC,Q  for  growth Inhibition  1n the  alga  Scenedesmus  subsplcatus  (Geyer et
al., 1985).  Deylllers et al.  (1986) compared toxldty of  the three chloro-
anlUnes with  PhotobacteMum  phosphoreum  and found  that 4-chloroan1l1ne was
most toxic, followed  by  3-chloroan1l1ne and  2-chloroan1l1ne.
4.4.   SUMMARY
    There were  three  studies   1n which  the  toxldty of all three  chloroanl-
Unes  were  compared  1n  the  same test  system,  but  these  studies  produced
conflicting  results.   Regarding  14-day LC5Qs  for  gupples,  2-chloroan1l1ne
was most toxic,  followed by 3-chloroan1l1ne; 4-chloroan1l1ne  was least  toxic
(Hermens  et  al.,  1985).   Yoshloka  et  al.  (1985),  however,   found   that
4-chloroan1l1ne  was   most   toxic   1n  Inhibiting  growth  of   the  protozoan
Tetrahymena  pyr1form1s.  followed  by  3-chloroan1l1ne  and  2-chloroan1l1ne.
Q028d                               -22-                             06/05/87

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Devlllers  et  al.   (1986)  found  that  4-chloroan1l1ne  was  most  potent  1n
Inhibiting luminescence  of  PhotobacteMum phosphoreum. followed by 3-chloro-
anlllne  and  2-chloroan1l1ne.   The  lowest reported acutely  toxic  concentra-
tions  were:   2  mg/l  4-chloroan1l1ne,  a  96-hour  LC5Q for  bluegllls  (Julln
and   Sanders,   1978);   1.35  mg/l   4-chloroan1l1ne,   a   24-hour   EC5_   for
Daphnla  carlnata (Hattorl  et  al.,   1984);  and  0.4  mg/l  4-chloroanlllne,  a
96-hour  EC,Q for  Scenedesmus  subsplcatus  (Geyer  et  al.,  1985).   A  14-day
study  by  Hattorl   et  al.  (1984)  Indicated  that reproduction  of  Daphnla
carlnata   was    affected   by   0.0427   mg/l   4-chloroan1l1ne   but  not   by
0.0135 mg/l.
0028d                               -25-                             05/15/87

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                             5.  PHARMACOKINETICS
5.1.   ABSORPTION
    In a  metabolism study of  3-chloroan1l1ne  with  rats,  -75% of a  10  mg/kg
oral  dose and 56%  of  a  150 mg/kg  oral  dose  were  excreted  1n the  urine  as
metabolites or unchanged  compound within  24 hours  (Boehme and  Crunow,  1969)
(Section  5.3.),  which  Indicates  that at  least 56-75% was  absorbed by  the
gastrointestinal  tract.
    Specific  data  regarding   the  oral  or  Inhalation  absorption  of  2- or
4-chloroan1l1ne could not be located  1n the  available  literature  as  cited In
Appendix A.  Oral absorption of  these Isomers 1s Indicated,  however,  by  the
occurrence of systemic toxldty following  oral exposure (Chapter 6).
5.2.   DISTRIBUTION
    Pertinent  data   regarding  the  distribution  of  absorbed   2-,   3- or
4-chloroan1l1ne could not be located  In the  available  literature  as  cited 1n
                                                               *              *
Appendix A.
5.3.   HETABOLISM
    An In  vivo metabolism study  was conducted  1n which single  10, 60  or  150
mg/kg doses  of 3-ch1oroan111ne  1n  Erdnussol  (vehicle) were  administered by
gavage  to male  albino rats  (Boehme  and  Crunow,  1969).   Urinary  analyses
conducted  24 hours  after  dosing  Indicated that  hydroxylatlon  of  the benzene
ring  was   the  primary  metabolic alteration,  as 2-am1no-4-chloropheno1  and
4-am1no-2-chlorophenol  and  their   glucuronlc  or   sulfurlc  add  conjugates
accounted  for  -16-25%  and  39-50%  of  the administered doses,  respectively.
Unchanged  3-chloroan1l1ne  accounted for  0.6-1.2% of  the  administered  doses.
Partial   acetylatlon of  the  amlno   groups  1n  the  phenolic  compounds  also
occurred but was  not quantified.
0028d                               -26-                             06/05/87

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    Klese  (1963) detected  3- and 4-chloronHrosobenzene In the blood  of  dogs
after  single  25-100  mg/kg Intravenous Injections of  3- and  4-chloroan1Hne,
respectively.   Also,  rabbit   hemoglobin-mediated  N-ox1dat1on  of  4-chloro-
anlUne has been demonstrated  In vitro (Golly and Hlavlca,  1983).
    N-hydroxylatlon  of  4-chloroan1l1ne was  demonstrated 1n J[n vitro  studies
with  rat  liver  mlcrosomes  (Uehleke,  1967;  Uehleke et al., 1971;  Pan  et  al.,
1979;  Lenk  and  Sterzl, 1981)   and  ram seminal vesicle mlcrosomes  (Golly  and
Hlavlca,  1985).   ln_  vitro metabolism of 4-chloroan1l1ne  with rabbit  liver
mlcrosomes  resulted  1n  N-hydroxylat1on and  dechlorlnatlon, producing  a  trace
amount of  4-hydroxyan1l1ne at  a high  substrate  concentration (Daly  et  al.,
1968) and hydroxylatlon of the  number 2 carbon atoms  (Lenk  and Sterzl, 1981).
    Although  metabolism studies of  2-chloroan1l1ne  could  not be  located  1n
the available literature,  N-ox1dat1on 1s expected to be  the  primary mecha-
nism,  as  1s  the case with 4-chloroan1l1ne,  because chlorine 1s  an  ortho-,
para-d1rect1ng  substUuent.    Likewise,   the  2- and  4-chloro  Isomers   are
expected  to have  lower  electron  ring  densities than  the 3-chloro  Isomer,
which makes  electrophlUc  aromatic (ring)  substitution less  likely  to  occur
1n  the  2- and 4-chloro Isomers  (Morrison and Boyd,   1966).   This  1s  consis-
tent with  the above  data  Indicating N-ox1dat1on of  4-chloroan1l1ne  and  ring
hydroxylatlon of 3-chloroan1l1ne as primary  metabolic pathways.
5.4.   EXCRETION
    The rat metabolism  study summarized  1n  Section  5.3. (Boehme  and  Crunow,
1969) Indicates that  substantial portions  of single  oral  doses  of 3-chloro-
anHlne are excreted In the urine as metabolites  within 24  hours.
0028d                               -27-                             05/15/87

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5.5.   SUMMARY
    3-Chloroan1l1ne appears to be readily absorbed  orally  by  rats;  up to 75%
of a  single  gavage dose was  excreted 1n the urine  predominately  as  metabo-
lites  within  24   hours  (Boehme  and  Crunow,   1969);  hydroxylatlon  of  the
benzene ring  was  the primary metabolic  alteration.   Iji vitro  studies  Indi-
cate  that  N-ox1dat1on  1s  the primary  metabolic  route  for  4-chloroan1l1ne.
Metabolism studies  of 2-chloroan1l1ne were  not located,  but  N-ox1dat1on 1s
expected to be the primary mechanism, as Is the case with 4-chloroan1l1ne.
0028d                                -28-                              06/05/87

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                                  6.   EFFECTS
 6.1.   SYSTEMIC TOXICITY
 6.1.1.   Inhalation   Exposure.    Pertinent   data   regarding   effects   from
 Inhalation exposure  to  2-,  3- or  4-chloroanlllne  could  not  be located In the
 available literature as cited 1n Appendix A.
 6.1.2.   Oral Exposure.
    6.1.2.1.   SUBCHRONIC  EXPOSURE — Subchronlc  range-finding  studies  were
 conducted with F344  rats  and  B6C3F1  mice to establish the dietary concentra-
 tions  of  4-chloroan1l1ne used  In  an  NCI  (1979) cardnogenldty  bloassay
 (Section  6.2.2.).   Groups  of  five  animals  of each  sex were  maintained  on
 diets  that  contained 0,  70,  145, 315,  680 or J465  ppm (rats)  and  0,  255,
 550,  1180,  2550,  5500,  8080,  11,830  or  17,380  ppm (mice) of 4-chloroan1l1ne
 for 4 weeks,  followed by  an observation  period  of 2 weeks.   Body weights and
 food  consumption  were  recorded  twice weekly throughout  the study,  and all
                           •             *
 survivors  were  necropsled upon  termination   of   the   study.    It  was  not
 Indicated  1f  the  necropsies  Included hlstologlcal  examinations.   In  rats,
 survival was  unaffected  by chemical exposure  and  there were  no treatment-
 related effects on body weight gain.  Enlarged  spleens  with plaque formation
 occurred In all  rats of  both  sexes  at  680  and 1465  ppm but In  none of the
 rats at lower doses.  All  male and  female mice  treated with 8080 ppm and 4/5
males  treated with  17,380 ppm  died,  but  no  cause  of  death  was  recorded;
 survival was  unaffected 1n the other groups.  There were no clear treatment-
 related effects on body weight  gain  In  the  mice.   Enlarged spleens occurred
 1n all 11,830 ppm  male  and all  17,380 female mice, but  1n  none of the other
 treated or control  mice.
0028d                               -29-                             06/05/87

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    The abstract  of a  Russian  study Indicated  that  oral  administration  of
3-chloroan1l1ne  at  0.1-0.2  the  L05Q  for  30  days  produced  methemoglobln,
n1trosylhemoglob1n and  sulfhemoglobin  (Vasllenko et al., 1972).   Additional
Information, Including the LD5Q, was not  reported.
    Pertinent  data  regarding  the  effects  of  subchronlc  oral  exposure  to
2-chloroan1l1ne could not be located 1n  the available  literature  as  cited In
Appendix A.
    6.1.2.2.   CHRONIC   EXPOSURE — Several    nonneoplastlc    effects    were
attributed  to  4-chloroan1l1ne  treatment 1n  an NCI   (1979)  cardnogenldty
bloassay.    Dietary  concentrations  of  250 or  500  ppm were  administered  to
F344 rats  and  2500  and  5000  ppm to B6C3F1 mice  for 78 weeks,  followed  by 24
                                                 *•
weeks  (rats)  and   13  weeks   (mice) of   observation   (Section  6.2.2.).   As
detailed In  Section 6.2.2., survival was  reduced In  the high-dose male rats,
and  mean  body weight  gain was  slightly depressed  1n the  high-dose  female
rats.  There were no  treatment-related  effects on survival  1n  the mice, but
mean body  weights  were  reduced markedly 1n  the high- and  low-dose mice of
both sexes.   Treatment-related  nonneoplastlc  lesions  Included  flbrosls  of
the  splenic  capsule with subcapsular mesenchymal proliferation  In male rats
(0/20,   45/49 and 38/49  In  the  control,  low- and  high-dose  groups,  respec-
tively) and  female  rats  (0/20,  30/48,  43/50).  Splenic  neoplasms  (Section
6.2.2.) appeared  to arise 1n  areas of  capsular or parenchyma 1  flbrosls In
the  rats.   In  mice,  there was moderate  to heavy Intracellular deposition of
Iron-positive  pigment  1n most  tissues,   particularly  the  spleen,  liver and
kidney, 1n both males (0/20,  35/50, 37/50) and females (0/18, 35/49, 33/42).
This pigment was  Interpreted  as  hemoslderln,  which  probably  resulted  from
excessive compound-Induced hemolysls.
0028d                               -30-                             05/15/87

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    Pertinent  data  regarding  the effects of chronic oral  exposure  to 2- and
3-chloroan1l1ne could not be  located  1n  the available  literature as dted 1n
Appendix A.
6.1.3.   Other  Relevant  Information.   A single  dose  gavage  LD5Q of  0.31
g/kg  was  determined  for   4-chloroan1l1ne   with  Carworth-Wlstar  male  rats
(Smyth et a!., 1962).
    Methemoglobln  percentages were  determined In  cats hourly  for  5  hours
following  administration of  single  oral   doses  of  0.25  mmol/kg  2-chloro-
anlUne  (31.9  mg/kg), 0.25 mmol/kg  3-chloroan1l1ne  (31.9 mg/kg)  or 0.0625
mmol/kg  4-chloroan1l1ne  (8.0  mg/kg)  (McLean et al.,  1969).  Groups  of  five
animals were assayed, and the overall  means of the  five posttreatment hourly
mean  methemoglobln  percentages  were  53.1, 47.3  and  45.2 for  2-,  3- and
4-chloroanlllne,  respectively,  which  Indicated that  the  4-chloro  Isomer 1s
the most potent methemoglobln Inducer.  The Investigators did not  state why
   •  -          *                                           _
they  administered  such  a low dose  of 4-chloroan1l1ne  relative  to  the other
Isomers.  Cats (adult) were used  1n  this study because they are  particularly
sensitive to methemoglobln  formation.  Aniline 1s a  recognized  methemoglobln
Inducer  (U.S.  EPA,  1984),  and many  substituted  anilines  produced methemo-
globln  1n  cats  (McLean  et  al.,  1969); aniline  compounds  1n  general  are
regarded as potential methemoglobln  Inducers (U.S.  EPA, 1984).   Abstracts of
Russian  studies  Indicate that  sulfhemogloblnemla  as well  as  hemogloblnemla
were  effects   of  single  or  several   dally  1ntraper1toneal  or  subcutaneous
Injections  of  2-,  3- or  4-chloroan1l1ne  1n  rats  or  mice  (Vasllenko  and
Zvezdal, 1972;  Zvezdal,  1972;  Nomura, 1975,  1980).
    Single   1ntraper1toneal   Injections  of   1.0  mmol/kg  (127.6  mg/kg)  of
2-chloroan1l1ne or  1.5  mmol/kg  (191.4 mg/kg)  of  3- or  4-chloroan1l1ne  were
nephrotoxlc   to male  F344  rats   (Rankln et al.,   1986).   Effects   Included


0028d                               -31-                              06/05/87

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decreased urine  volume,  elevated BUN concentration  and  decreased basal and
lactate-stlmulated p-am1noh1ppurate  accumulation  by  renal  cortical  slices.
6.2.   CARCINOGENICITY
6.2.1.   Inhalation.   Pertinent  data   regarding   the  cardnogenlcHy  of
Inhaled  2-,  3- or  4-chloroan1l1ne  could  not  be  located 1n  the available
literature as cited 1n Appendix A.
6.2.2.   Oral.   The  cardnogenlcHy of  4-chloroan1l1ne  was   evaluated  1n a
feeding  study  using  Fischer  344 rats and  B6C3F1 mice (NCI,   1979).   Results
from  this  assay were  also  reported by  Ward  et al.(1980),  Ward and Resnlk
(1981) and Goodman et  al. (1984).   Technical-grade  compound  was  administered
to groups of fifty -6-week-old animals of  each  sex  at  diet concentrations of
250 or 500 ppm (rats)  and 2500 or 5000 ppm (mice)  for 78 weeks,  followed by
observation  periods  of  24   weeks   (rats)  and   13  weeks   (mice).   Twenty
untreated animals of  each sex  and species served as  controls.   Body  weights
were  recorded  weekly  for the  first  6  weeks,  every  2  weeks  for  the  next 12
weeks  and  at monthly  Intervals  thereafter for  the remainder of  the  study.
Necropsies Including  comprehensive  hlstologlcal  examinations were conducted
on  all  animals  that   were moribund, had  palpable  masses   that  jeopardized
their  health,  were  killed at the end of the study  or  were found dead during
the study.
    Slight mean body weight  depression occurred  1n  the high-dose female rats
after week 40  of  treatment,  but  treatment-related  effects  on body weight did
not  occur 1n   the  males  (NCI,   1979).   There  was  a significant  positive
association  (p«0.0294, Tarone  test)  between dosage  and mortality 1n  the male
rats  (reflecting  reduced high-dose  survival  after  60 weeks of treatment),
but not  In the female rats.   Adequate numbers of  both male  and female rats.
0028d                               -32-                             06/05/87

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however,  survived  until  the  end  of  the  study  to  be  at  risk  for  late-
developing  tumors.   Increased  Incidences of  splenic neoplasms,  consisting
primarily of  flbromas,  occurred In the high-dose male rats.   As  detailed In
Table 6-1,  there  was a  significant positive  trend  (p=0.001) between  compound
administration  and  Incidences  of  pooled splenic  tumors  (Cochran-ArmHage
test)  In  the males, and  the Incidence  1n  the high-dose group was  signifi-
cantly  Increased  (p=0.02)  when  compared with  Incidences  1n the  controls
(Fisher Exact test).   There was  a significant positive  association  between
dose  and  the combined Incidence  of  mesodermal  cancers:   flbromas,  flbro-
sarcomas,  hemanglosarcomas,  osteosarcomas or  sarcomas NOS  of the spleen or
splenic  capsule.   Tumor   Incidences   were   0/20,  0/49  and  10/49  for  the
control,  low- and high-dose groups,  respectively.   However,  the  NCI  report
notes that  a  metastaUc sarcoma  not  otherwise specified (NOS) was  observed
1n the  splenic  capsule  of  one control male  rat; however,  no primary sarcoma
was detected.   If 1t  1s assumed that  the missing  tumor was In the spleen of
this control  rat  thereby  elevating the control Incidence for  splenic  tumors
to 1/20,  making  the control  to high  dose  comparison no  longer  significant
(p=0.10)  using  the Fischer  Exact  Test.   However, NCI  also notes  that  the
historical  Incidence of  sarcomas  NOS  1s  1/360 while the historic  Incidence
of  splenic  flbromas,  fIbrosarcomas,   osteosarcomas  and   hemanglosarcomas  Is
0/360.  Therefore,  NCI  felt with  these  additional  arguments that  the data
suggests a  compound-related  Increase  1n  the  Incidence of splenic  tumors  for
the male rat.
    In contrast  to  the rats, distinct mean  body weight  depression  occurred
In dosed male and female mice (both  dose  groups)  throughout the B6C3F1 mouse
study (NCI,  1979).  There was  no  treatment-related mortality  1n  either sex,
however, and  adequate numbers of animals  survived  until  the end of the study


0028d                               -33-                             07/22/87

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                           -35-
                                                                          05/15/87

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to be  at  risk for late-developing tumors.  There was  a  significant  positive
trend  (p=0.01)  between compound  administration  and Incidences of  hemanglo-
sarcomas  and  combined  Incidences  of hemanglosarcomas and hemanglomas  1n  the
female mice  (see  Table 6-1).   The p value for the  Fisher Exact  test compar-
ing  the  combined Incidences  of  hemanglosarcomas   and  hemanglomas  In  the
female high-dose  group  with  the  Incidence 1n the control group  was  signifi-
cant  at   p-0.046.  The combined  Incidences  of  hemanglosarcomas  and  heman-
glomas In the male mice were  dose-related  (see  Table 6-1),  but  neither  the
Cochran-Armltage trend test nor the Fisher Exact  Test  were  significant.   The
NCI  concluded that  the  above data  are  "Insufficient  for  correlating"  the
occurrence of  the hemanglomatous  tumors to treatment.   Consideration  of  the
                                                 •f
"apparent" dose-related  effect In both  sexes  and  the historical  Incidences
for combined  hemanglosarcomas and hemanglomas In male  and female  B6C3F1  mice
(8/262 and 7/260,  respectively;  ~3X),  however,  suggests a  positive  assoda-
                                                       •
tlon between  hemanglomatous  tumors  and  p-chloroanlUne  administration (NCI,
1979).  There  was  also a  positive  trend (p=0.01)  between  compound  adminis-
tration  and   combined   Incidences  of  hepatocellular  carcinoma  and  hepato-
cellular  adenoma  1n  the female  mice  (see Table  6-1),  but  the  Fisher  Exact
Tests were not  significant.   Moreover,  the Incidences observed  In  the liver
were not unusual when compared with the historical control  data.
    NCI (1979)  concluded that  there was suggestive  evidence  In  the male rat
and  female  and male mouse.   The prollferatlve  and neoplastlc  lesions  were
hlstologtcally  Identical   to  those  Induced  1n   Fisher   344  rats by aniline
hydrochlorlde and o-tolu1d1ne hydrochlorlde.
    The  NTP  Initiated  a  gavage bloassay  of  4-chloroan1l1ne  to  further
clarify  the  results  of   the  NCI  (1979)  study.   This  bloassay  Involves
treatment of  rats of both  sexes  at  doses of  0,  2, 6 or 18 mg/kg/day and mice


0028d                               -36-                             07/21/87

-------
 of  both sexes  at  doses of  0,  3,  10 and  30  mg/kg/day for 2  years  (Canter,
 1985).   Preliminary  findings  Indicate  that  treatment with  4-chloroan1l1ne
 Induced  an Increased  Incidence  of  splenic sarcomas  In the male  rats.   The
 study  1s currently  1s  1n the Pathology Working Group phase (MTP, 1987).
    Pertinent  data  regarding the oral carclnogenldty  of  2-  or 3-chloroan1-
 Une could not  be located 1n the available literature as cited In Appendix A.
 6.2.3.   Other  Relevant  Information.   4-Chloroan1l1ne   was   tested   1n  a
 Strain A mouse  pulmonary  tumor  assay  with  negative results (Maronpot et al.,
 1986).   In this test,  groups  of  ten 6- to 8-week-old  Strain  A/St mice were
 given  1ntraper1toneal  Injections  of  25,  57.5  or 60  mg/kg   1n  trlcaprylln
 vehicle, 3 times/week  for 8  weeks;  the  two highest doses  represented maximum
 tolerated  doses.  Macroscopic  evaluation of the lungs  after  a 16-week post-
 treatment  Incubation  period  showed that  tumors  occurred   1n only  one  of the
 low-dose males.  Survival  was affected only  In  the  male  57.5  mg/kg  dose
                                            •
 group  (4/10 were alive at study termination).
 6.3.   MUTAGENICITY
    MutagenlcUy and  other  short-term  assays have  been   conducted  with 2-,
 3- and 4-chloroan1l1ne.  The results  of  these assays  are  detailed In  Tables
 6-2, 6-3 and 6-4 and are summarized briefly below.
    2-Chloroan1l1ne produced reverse mutations  In a  study with Asperglllus
 nldulans when  tested  without  metabolic  activation   (Prasad,  1970)  and  In
 studies  of DNA  repair  In  DNA repair  deficient  and  proficient  strains  of
 Escher1ch1a coll  (pol  A",  pol A*)  (Rosenkranz and  Polrler,  1979;  Po1r1er
 and de  Serres,  1979;  Lelfer  et  al.,  1981).  Negative  results were obtained
 In  reverse mutation  assays  with various  strains  of  Salmonella typhlmurlum
when  tested  by  different methods,  1n  a  mltotlc  recombination  assay  with
 Saccharomyces   cerevlslae.  In  an  unscheduled  DNA  synthesis  assay  with rat


0028d                               -37-                             07/21/87

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hepatocytes  and  1n  a  sperm  head  abnormality  test  with  mice  treated  by
1ntraper1tonea1  Injection  (see Table  6-2).   Also,  2-chloroan1l1ne  did  not
produce  neoplastlc  transformation  In  cultured  hamster  embryo  cells  (see
Table 6-2).
    3-Chloroan1l1ne  produced   reverse  mutation   In  A.  nldulans  when  tested
without  metabolic activation  (Prasad,  1970),   but  was  not  mutagenlc  for
various strains of £. typhlmurlum when  tested with  or without  activation and
did not  produce unscheduled ONA synthesis  1n  rat hepatocytes \n_  vitro (see
Table 6-3).
    4-Chloroan1l1ne has been  tested 1n numerous  short-term genotoxlclty and
cell transformation assays.  Positive responses  occurred  1n a  single reverse
mutation assay with A, nldulans (Prasad, 1970),  1n  a single  reverse  mutation
assay  with  cultured  L5178Y mouse  lymphoma  cells   (NTP,  1983)  and 1n  DMA
repair  assays  with  E_.  coll (Lelfer  et al., 1981;  Rosenkranz and  Polrler,
1979;  Polrler and  De Serres, 1979)  and  cultured  rat  hepatocytes  (Williams et
al.,  1982).    Mostly  negative  results  were reported In  reverse  mutation
assays  with  S.  typhlmurlum  (see   Table   6-4).   4-Chloroan1l1ne  produced
neoplastlc  transformation   1n  Rauscher  leukemia virus-Infected  rat  embryo
cells  (Traul et  al.,  1981;  NTP.  1983)  but elicited  conflicting  results with
hamster embryo  cells  (Plenta and Kawalek,  1981; Plenta.  1980) and  negative
results with mouse BALB/c  3T3 cells  (NTP,  1983).
    The  weight of  evidence Indicates  that  the results  of   the  short-term
assays   of    2-,   3- and    4-chloroan1l1ne    should   be   regarded   as
Inconclusive.Positive responses were  reported  In several test  systems, but
1n  many  cases   these  data  are limited  by  conflicting  results or  a lack of
corroborating  studies.    Evaluation  of the  mutagenlcUy/clastogenldty  of
2-chloroanlllne and 3-chloroanlllne Is  further  limited by a  lack  of variety
of assay types.

0028d                               -44-                             07/21/87

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6.4.   TERATOGEMICITY
    Specific  Information  regarding  the  teratogenldty  of  the  monochloro-
anlllnes  could  not  be  located  1n  the  available  literature as  cited  In
Appendix A.   The  U.S.  EPA  (1984)  has  suggested,  however,  that  aniline
compounds  may   cause  teratogenldty   by   possible   anoxia   resulting  from
methemoglob1nem1a.
6.5.   OTHER REPRODUCTIVE EFFECTS
    Specific  Information  regarding  the reproductive  effects  of the  mono-
chloroanlUnes could  not  be located  1n the available  literature  as  cited 1n
Appendix A.  The U.S. EPA  (1984)  believes,  however, that aniline  compounds
may  cause adverse  reproductive effects  on  the  basis  of   Information  that
repeated  subcutaneous Injection of  aniline Interferes  With steroldogenesls
1n the rat uterus and that  repeated  oral administration of  4-chloro-3-n1tro-
anlllne causes sperm degeneration and an Increase In testes  weights  In rats.
6.6.   SUMMARY
    Pertinent  data   regarding   the  effects  of  Inhalation   exposure  to  the
chloroanHlnes could  not  be located  In the available  literature  as  cited In
Appendix A.  Effects  of  oral administration of  chloroanlUnes  are limited to
4-chloroan1l1ne.    In  a  subchronlc  dietary  study  of   4-chloroan1l1ne,  rats
treated at >680  ppm  had  enlarged spleens with  plaque formation; rats treated
at <380 ppm did  not  (NCI,  1979).   Enlarged  spleens  also occurred  1n mice fed
at dietary  levels  >11,830  ppm.  At  8080 ppm,  all  the mice died of  unknown
causes.  No effects  were observed at  5500 ppm.
    Based on  an  acute oral study  using cats,  4-chloroan1l1ne was  -4 times
more  potent  as  a methemoglob1nem1a  Inducer than were  2- or 3-chloroan1l1ne
(McLean et al.,  1969).
0028d                               -45-                             07/21/87

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    4-Chloroan1l1ne was  administered  1n the  diet  to rats at  concentrations
of  250  or 500  ppm and mice at  concentrations  of 2500 and  5000 ppm for  78
weeks,  followed by  observation  periods  of  24  and  13  weeks,  respectively
(NCI, 1979).  Effects  In the rats  Included  reduced  survival  1n the  high-dose
males,  reduced  body weight gain  In the high-dose  females,  flbrosls of  the
splenic  capsule with  subcapsular  mesenchymal proliferation  In  most of  the
treated males and  females,  and  Increased Incidences of splenic  flbromas  and
sarcomas  In  the  high-dose males.   Effects  In  the  mice  Included  markedly
reduced body weight gain 1n the high- and  low-dose  males  and females,  1ntra-
cellular  deposition  of hemoslderln 1n  many  tissues  In  most of the  treated
males  and  females  and  hemanglomatous  tumors  In  the  treated  males  and
females.   NCI   (1979)  concluded  that  these  findings  are  Insufficient  to
establish  carclnogenldty  of  4-chloroan1l1ne In either  rats  or mice.   The
splenic tumors  1n  the rats were  considered strongly suggestive of  carclno-
genldty,  however, because  of  the rarity  of  these tumors  In  historical
controls.   Furthermore,  preliminary  results of  an  NTP  gavage study  using
rats and  mice  Indicate an  Induction of  splenic  tumors In  male rats (Canter,
1985).   4-Chloroan1l1ne  was Inactive  1n a  Strain  A  mouse pulmonary  tumor
assay (Haronpot et al., 1986).
    Specific Information regarding  the  carclnogenldty of  2- or 3-chloroan1-
Une could not  be located In the available literature as  cited In Appendix A.
Evidence  for  the  N-ox1dat1on  of monochloroanllines  (see Section  5.3.)  and
methemoglobln Induction by  monochloroanlUnes (McLean et  al.,  1969) provides
an  Indication  of  potential  carclnogenldty, however, as  Induction  of both
carclnogenldty  and methemoblob1nem1a  by  aniline  and  substituted  aniline
compounds  Is  attributed  to the  formation  of  N-oxIdlzed metabolites  (U.S.
EPA, 1984).


0028d                               -46-                             07/21/87

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     GenotoxIcHy  and  cell  transformation  testing of  2-,  3- and  4-chloro-
anlllne  produced  positive responses  In several  assays.   Conflicting results,
a  lack of corroborating  data  and,  In the case  of 2- and  3-chloroan1l1ne,  a
limited  variety of  assay types Indicate  that  evidence for  genotoxlclty  of
the  chloroanHlnes should be regarded as Inconclusive.
     Specific  Information  regarding  the teratogenldty  or  other  reproductive
effects  of  the monochloroanllines   could  not  be  located  1n the  available
literature as  cited  In Appendix A;  however, the  potential  for  these effects
has  been suggested by  the  U.S. EPA  (1984)  on  the basis of  possible  anoxia
resulting  from methemogloblnemla and  reproductive  effects  produced by other
aniline compounds.
0028d                               -47-                             07/21/87

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                    7.  EXISTING GUIDELINES AND STANDARDS
7.1.   HUMAN
    Pertinent guidelines and  standards,  Including  EPA ambient water and  air
quality  criteria,   drinking  water   standards,   FAO/WHO   ADIs,   EPA  or   FDA
tolerances  for  raw agricultural commodities  or  foods, and  ACGIH,  NIOSH  or
OSHA  occupational  exposure  limits  could  not be  located  In  the available
literature as dted 1n Appendix A.
7.2.   AQUATIC
    Guidelines  and  standards  for  the protection  of  aquatic organisms  from
the  effects  of  chloroanlUnes  could  not  be   located   In  the available
literature as dted In Appendix A.
0028d                               -48-                             06/05/87

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                              8.   RISK ASSESSMENT

    Chronic  and  subchronlc toxldty  data  were available only  for  4-chloro-
anlllne;  therefore,  risk  assessment  values  cannot  be derived  for  2- or
3-chloroan1l1ne.   Furthermore,  It 1s  not appropriate  to  derive  risk  assess-
ments  for  2- or  3-chloroan1l1ne by analogy  to  4-chloroan1l1ne  because their
dose-responses  for  toxic  effects  may  be  significantly   different.   For
example, an  acute oral study  1n  cats Indicated  that  4-chloroanlllne  was -4
times  more  potent  as  an  Inducer  of  methemogloblnemla than  were  2- and
                                                                            •
3-chloroan1l1ne (McLean et a!., 1969).
8.1.   CARCINOGENICITY
8.1.1.   Inhalation.   Pertinent   data  regarding' the   carclnogenldty   of
Inhaled  2-,  3- or  4-chloroan1l1ne could  not  be located  In the  available
literature as cited In Appendix A.
8.1.2.   Oral.   An  NCI   (1979)  carclnogenldty  bloassay was -conducted  In
which groups of 50  F344 rats  of  each  sex were maintained on diets containing
250  or  500  ppm  4-chloroan1l1ne  for  78 weeks,  followed by an  observation
period of  24 weeks.   Groups  of  50  B6C3F1  mice  of  each sex were  similarly
treated with  2500 or 5000  ppm 4-chloroanlllne for 78 weeks, followed by 13
weeks  of  observation.  Twenty untreated  animals of  each  sex and  species
served as controls.   As detailed 1n Section  6.2.2.  and  Table 6-1,  there was
a positive association  between treatment and the occurrence of  Hbromas of
the  spleen  1n   rats   (significant   Cochran-ArmHage   test);  however,  the
Incidence  1n  the  high-dose   group   was not  significantly  Increased  when
compared with  the control group  (Fisher Exact test).    There was  a  signifi-
cant positive  trend  (p«0.001)  between  dose  and  the  combined  Incidence of
flbromas,  fIbrosarcomas,  hemanglosarcomas,  osteosarcomas or  sarcomas  NOS of


0028d                               -49-                             07/17/87

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the  spleen  or splenic  capsule.   The Fisher  Exact  Test comparing  the  high-
dose  group  with  the concurrent  controls  was  also  significant  at  p=0.02.
Tumor  Incidences  were 0/20, 0/49 and  10/49 for the  control,  low-  and  high-
dose groups,  respectively.   However,  the NCI report  notes  that a  metastatlc
sarcoma  NOS  was  observed  In the splenic  capsule  of  one  control   male  rat;
however, no primary  sarcoma  was detected.   If  1t  1s  assumed that  the missing
tumor was 1n  the  spleen of  this control  rat  elevating the control  Incidence
for  splenic  tumors  to  1/20, the control  to high  dose comparison  would  no
longer  be  significant using  the  Fisher Exact  Test   (p=0.10).  However,  NCI
also notes that  the  historical  Incidence of sarcomas  NOS  Is  1/360  while the
historic  Incidence  of  splenic  flbromas,  flbrosarcomas,  osteosarcomas  and
                                                 ^
hemanglosarcomas  1s   0/360.   Therefore,  NCI  felt  that  the observed  data
suggests a compound-related  Increase In the Incidence of splenic tumors.
    There  was  a  significant  dose-related   positive  trend  (p-0.01)  for
hemangloma  or  hemanglosarcoma  "at  all  sites   In  the  female  mice and  the
Incidence In  high-dose females  was significantly  greater (p-0.04)  than  1n
the  controls.   The  combined  Incidences  of hemanglosarcomas  and  hemanglomas
In  the  male  mice  were  Increased  1n a  dose-related  manner,  but neither the
trend test nor Fisher Exact comparisons were significant at the p=0.05 level.
    The  occurrence  of flbromas and sarcomas  In  the  spleens  of  the treated
male rats was considered  strongly  suggestive  of  carc1nogen1c1ty.   Further-
more,  preliminary results  of  a  study  by  NTP  In which rats and  mice were
treated  by   gavage  with   4-chloroan1l1ne  Indicate   that   treatment  Induced
splenic  sarcomas  1n  male  rats (Canter,  1985).  The  hemanglomatous  tumors In
the  treated mice  of  both  sexes may  also have  been associated with 4-chloro-
anlllne  treatment  In the  NCI  (1979) study,  as these  tumors  showed a  trend
and statistical significance In the female mouse.


0028d                               -50-                             07/21/87

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    Pertinent  data  regarding the oral carclnogenlcHy of  2-  or  3-chloroan1-
 Une could not be located In the available literature as  cited In Appendix  A.
 8.1.3.   Other  Routes.   4-Chloroan1l1ne was  Inactive In  a  Strain  A mouse
 pulmonary tumor assay (Maronpot et a!., 1986).
 8.1.4.   Weight  of  Evidence.   The rat  and mouse  carclnogenldty  bloassay
 evidence combined with  the  Inconclusive  mutagenldty  data  would  suggest  that
 p-chloroanHlne  1s  In  the  C  to  B2  range  according to  EPA's  cancer  risk
 assessment guidelines.   The  positive  male rat  data with the  positive  female
 mouse  data  gives two species,  albeit  almost marginally  so In the mouse and
 with some uncertainty In the rat.
    The  suggestion  of a  positive trend  In  the  male mouse using  historical
 controls  Is  not  Inconsistent  with the  other  observations.  The  pathologic
 observations  are consistent with  similar  observations  made   by  NCI  with
 aniline  hydrochlorlde and  o-toluldlne  hydrochlorlde.   Given  that a  repeat
 bloassay 1s  underway  the results  of  which are qualitatively reported to  be
 similar  for   the  male  rat, a  provisional  Group  C  weight  of  evidence  Is
 assigned to  4-chloroan1l1ne, provisional  to the  extent  that  a review  should
 be  done  when  the  new  bloassay  Is  finished  to   finalize  the  weight  of
 evidence.  There  are  also  reasons  to consider  a B2 ranking; however,  this
 should  be  reserved  for   the  time  when  the results from  the new  NTP  bloassay
 can be  utilized.   The lack  of  carclnogenldty data  for 2- and  3-chloroanl-
 llne Indicates that  these compounds should be categorized In EPA  Group D.
8.1.5.   Quantitative Risk Estimates.
    8.1.5.1.    INHALATION — Data   regarding     the    carclnogenldty    of
4-chloroan1l1ne  by   the  Inhalation   route  were  not  available.   Precedent
exists  for   extrapolating  from  the  Inhalation   route   to the  oral  route,
particularly  when  differential  absorption  data  are available  (U.S.  EPA,
0028d                               -51-                             07/22/87

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1980).   However,  extrapolation  from the oral  route  to the  Inhalation  route
Includes  the  additional   uncertainty   of  possible  direct  effects  of  the
Inhaled  compound  on  the  pulmonary  system.   In this  Instance,  since  rela-
tively  little  Is  known concerning  the  pharmacoklnetlcs and  pharmacodynamlcs
of 4-chloroan1lk1ne, a formal extrapolation 1s not  pursued.
    8.1.5.2.   ORAL —The   strong  suggestion  that   4-chloroan1l1ne   was
carcinogenic  In  male  rats  and  female  mice  provides a basis  to evaluate  a
q *  for oral  exposure.   The data  used to calculate  the  q * are  presented
1n  Appendix B.  The  transformed  doses were  calculated by  multiplying  the
                                        •
dietary  concentrations by  0.05  (assuming  that a rat consumes  a  dally amount
of  food equal  to 5%  of  Its body  weight)  and  by the ratio of the  length of
                                                 *•
exposure  to  the  length  of  the  experiment  (78  weeks/102  weeks).    The
unadjusted  q *  was  calculated  using  the  computerized   multistage  model
developed   by   Howe   and   Crump   (1982).    The  human   q,*   of   3.5xlO~2
(mg/kg/day)"1  was  calculated  by  multiplying   the  unadjusted  q,*  by  the
cube  root  of the  ratio  of  the  reference  human body  weight (70 kg)  to  the
mean  weight  of  the male rats {0.38 kg, estimated  from the  growth  curves In
the  study)  and by  the cube  of  the ratio  of  the  Hfespan  of  the  rat  (104
weeks)  to the length of the experiment (102 weeks).
    Assuming that  a 70 kg person  drinks  2 I water/day,   the  concentrations
of  4-chloroan1l1ne  1n drinking water  associated with an  Increased lifetime
risk  of  cancer  at   risk   levels  of  10'5,   10~*   and   10~7  are  lxlO~a,
lxlO~a and 1x10"* mg/l, respectively.
    For  comparative   purposes,   a  q,*   value  was   calcualted  using  the
Incidence of hemanglomas  and hemanglosarcomas 1n  female mice.   The data are
shown   1n   Appendix  B.     A  somewhat   lower  potency  value  of   6.5x10""
0028d   ..                           -52-                             07/21/87

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 (mg/kg/day)"1  was  obtained.   Therefore,  the  higher  value  based upon  the
 rat  data  1s  chosen to  approximate the  potency  of 4-chloroan1l1ne  for  the
 purposes of this risk assessment.
    The  q,*  should be regarded  as  provisional until the  results  of  the  NTP
 study, which may provide more definitive evidence, become available.
 8.2.   SYSTEMIC TOXICITY
 8.2.1.   Inhalation  Exposure.   Pertinent data  regarding  the  toxldty   of
 Inhaled  2-,  3- or  4-chloroan1l1ne  could not  be  located  In  the available
 literature  as  cited  1n  Appendix A.   Calculation  of  chronic  or  subchronlc
 Inhalation RfOs are precluded by the lack of these data.
 8.2.2.   Oral Exposure.
    8.2.2.1.   LESS   THAN  LIFETIME   EXPOSURES   (SUBCHRONIC) — Subchronlc
 range-finding  toxldty  studies of  4-chloroanlllne were conducted with F344
 rats  and B6C3F1  mice  as  part  of  the  NCI  (1979)  cardnogenldty bloassay.
 Groups of  five animals of  each  sex  were maintained on diets that  provided 0,
 70,  145,  315,  680 or 1465  ppm (rats)  and  0, 255,  550,  1180,  2550,  5500,
 8080,  11,830  or  17,380  ppm  (mice)  of compound for  4 weeks,  followed  by an
 observation period of 2  weeks.   Necropsies  conducted on survivors at the end
 of the study  showed that enlarged  spleens with plaque  formation  occurred In
 all rats of  both  sexes  at <680 ppm, but  1n  none  of  the rats at lower doses.
 There were no  treatment-related  effects on  rat body  weight  or survival.   As
 detailed  1n  Section  6.1.2.1.,  mortality and  enlarged spleens  occurred In
mice  of  both  sexes at  <8080 ppm.   There  were  no  clear treatment-related
effects on body weight  1n the mice.  The  cause of the  mortality  1n the mice
was not specified, necropsies were  only  conducted  on surviving rats and mice
and  1t  was  not   Indicated  1f  the  necropsies  Included hlstologlcal  exami-
nations.
0028d                               -53-                             07/21/87

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    8.2.2.2.   CHRONIC   EXPOSURES  —  4-chloroan1Hne   showed   evidence  of
carclnogenldty  1n  rats  In the NCI (1979)  study  and  a q * was derived.  An
RfD  could  be  based  on nonneoplastlc  effects  1n  the  NCI  (1979)  study.  In
this study,  groups  of  50 F344 rats of each  sex were  treated In the  diet at
concentrations  of  250  or  500  ppm for  78 weeks,  followed  by 24  weeks of
observation.   Groups of  50 B6C3F1  mice  were similarly treated  at concentra-
tions of 2500  or 5000  ppm  for  78 weeks,  followed  by 13 weeks of observation.
Control  groups  consisted of  20  untreated animals  of  each sex and  species.
As  detailed  1n Section  6.2.2.,  survival was  reduced  In the high-dose  male
rats,  average  body  weight  was decreased  In  the high-dose  female  rats  and
average  body weights  were decreased  1n  both sexes   of  mice  at  both  dose
levels.   Treatment-related  nonneoplastlc   lesions  of  the  capsule  of  the
spleen  (focal  flbrosls  with subcapsular mesenchymal proliferation)  occurred
In  most of  the  treated  rats  (see  Section  6.1.2.2.).   Moderate  to  heavy
Intracellular deposits of  pigment  occurred  In  many  tissues,  particularly the
spleen,  liver  and kidney,  1n most of  the treated mice.   This pigment  was
thought  to  be  hemoslderln,   resulting  from excessive   treatment-Induced
hemolysls.    The  dietary  levels of  250 ppm  1n  the rat  study and 2500 ppm 1n
the mouse study therefore represent LOAELs.
    If  1t  Is assumed that dally food consumption In  the rats  and mice  Is  5
and 13% of body weight,  respectively, then the LOAELs  are  equivalent to 12.5
and  325 mg/kg/day,  respectively.   However,   1n  view  of  the  evidence  for
carclnogenldty, albeit limited, an RfD  1s  not estimated.  The  final  results
of  the  NTP  study  may  provide more definitive  evidence,  as  preliminary
results suggest that rats treated by gavage developed spleen  sarcomas.
0028d                               -54-                             07/21/87

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                           9.   REPORTABLE QUANTITIES
9.1.   BASED ON SYSTEMIC TOXICITY
    An NCI  (1979)  carc1nogen1c1ty bloassay was conducted  In  which groups of
20,  50 and  50 F344  rats  of  each  sex  were  exposed to 0,  250 and  500 ppm
4-ch1oroan111ne  In  the  diet,  respectively,  for  78 weeks,  followed  by  24
weeks  of  observation.   Groups of 20,  50 and  50  B6C3F1  mice of each sex were
exposed  similarly  to  0,  2500  and  5000  ppm,  respectively,  for   78  weeks,
followed  by 13  weeks  of  observation.   As  detailed  1n  Section  6.2.2.  and
summarized  In  Table 9-1,  nonneoplastlc  effects 1n  the  rats Included reduced
     •
survival  1n the high-dose  males,  decreased body  weight  gain In the high-dose
females  and  nonneoplastlc  proHferatlve  lesions   of  the  spleen  In  most
animals of  both sexes  at both doses.   Effects In the mice  Included decreased
body weight  gain  and  Intracellular  deposits  of  pigments  1n  many  tissues In
both  sexes  at  both doses.   This pigment was  particularly  evident  In the
spleen,  liver  and  kidney  and was thought to be hemoslderln  resulting from
excessive treatment-related hemolysls.
    The most severe effects,  which are  considered  for  RQ  determination, are
decreased survival  and splenic  lesions.  The lowest equivalent  human doses
at which  these effects  occurred  are  4.4 and 1.9  mg/kg/day, respectively (see
Table  9-1).   Multiplication  of  these  doses  by  70  kg yields  MEOs  of 308
mg/day for  decreased  survival  and  133  mg/day  for  splenic lesions,  and the
RV.s  are calculated  to   be  1.8  and  2.3,   respectively.   Pronounced  life
shortening  warrants an  RV   of  10.    Selection  of  an RV   for  the splenic
                           c                               C
lesions  Is  complicated because  organ  function  was  not  evaluated.   An RV
of  6,   typically   reflecting   pathologic  alterations  without  a  detectable
decrement In  organ  function,  1s assigned.   Multiplication  of the  RV.s  by
0028d                               -55-                             06/05/87

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-56-
                                                                     06/05/87

-------
 the  RVgs  yields  CSs  of  18  for  life  shortening and  14  for  the  splenic
 lesions  (Table  9-2).   Both  of  these  CSs correspond to an RQ of 1000, but the
 higher CS  1s the preferred value (Table 9-3).
    Calculation of  RQs for  2- or 3-chloroan1l1ne  are  precluded  by a lack of
 relevant  toxldty  data (Table 9-4).   Furthermore, It 1s  not  appropriate to
 derive  RQs for  2- and 3-chloroan1l1ne  by  analogy  to  4-chloroan1l1ne because
 dose-responses  for  their  toxic effects may  be  significantly different.  For
 example,  an  acute oral study  using  cats  Indicated that  4-chloroan1l1ne was
 -4  times  more  potent as  an  Inducer  of  methemogloblnemla  than  were  2- or
 3-chloroan1l1ne.
 9.2.   BASED ON CARCINOGENICITY
    There  was  evidence  that 4-chloroan1l1ne was  carcinogenic  In  male rats
 and  female mice  1n  the  NCI  (1979)  study,  placing  4-chloroan1l1ne  1n EPA
 Group  B2  to C  range  (see  Section  8.1.).  While  some  might  consider  a B2
 category appropriate,  the  expectation  of  results  from a  repeat NTP bloassay
 due  In  early 1988  should  be  used  to  formulate  a final  weight  of evidence
 classification.   At  present the compound  1s considered to  be a provisional
 Group  C.  The  response data  provides  a  basis   to  derive  an  RQ  based on
 carclnogenlclty.  An  F factor  was  calculated  using  the data  1n Table 9-5.
 The  method  for calculating  the  transformed  doses   was  given   In  Section
 8.1.5.2.   The  unadjusted  1/ED10 was  calculated using the  multistage model.
 The  F  factor of  4.1X10"1   (mg/kg/day)"1  was calculated  by  multiplying the
 unadjusted  1/ED,Q  by  the   cube  root  of   the  ratio  of  the  reference  human
 body weight  (70 kg)  to the body weight of  the  rat (0.38  kg) and by the cube
 of the ratio of the Hfespan of the  rat   (104 weeks)  to  the duration of the
 study  (102  weeks).   For   comparative  purposes,  an  adjusted  1/ED-m
0028d                               -57-                             07/21/87

-------
                                  TABLE 9-2

           Oral Composite Scores  for  4-Chloroan1l1ne  Using  the  Rat*
Animal Dose
(mg/kg/day)
 Chronic
Human MED
(mg/day)
RVd
Effect
RVe    CS     RQ
   25

   12.5
   308       1.8    reduced survival          10     18    1000

   133       2.3    nonneoplastlc lesions      6     14    1000
                    In the spleen
*Source: NCI, 1979
0028d
                     -58-
                                         07/17/87

-------
                                   TABLE 9-3
                                4-Chloroan1l1ne
           Minimum Effective Dose (MED)  and Reportable Quantity (RQ)

Route:                  oral
Dose*:                  308 mg/day
Effect:                 reduced survival
Reference:              NCI, 1979
RVd:                    1.8
RVe:                    10
Composite Score:        18
RQ:                     1000
*Equ1valent human dose
0028d                               -59-                             07/17/87

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                                  TABLE 9-4
                            2- and 3-Ch1oroan1l1ne
           Minimum  Effective  Dose  (MED) and Reportable Quantity  (RQ)


Route:
Dose:
Effect:
Reference:
RVd:
RVe:
Composite Score:
RQ:                     Data are not sufficient for deriving an RQ.
0028d                               -60-                             07/17/87

-------
                                   TABLE  9-5
             Derivation of Potency Factor (F) for 4-ChloroanHlne
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle or physical state:
Body weight:
Duration of treatment:
Duration of study:
Llfespan of animal:
Target organ:
Tumor type:
Experimental doses/exposures (ppm):
Transformed doses (mg/kg/day):
Tumor Incidence:
Unadjusted 1/ED10:
Adjusted 1/ED-io (F Factor):
        NCI, 1979
        oral
        rat
        F344
        male
        diet
        0.38 kg (measured)
        78 weeks
        102 weeks
        104 weeks
        spleen
        f1broma/fIbrosarcoma
        0             250
        0             9.6
        0/20          0/49
        6.802xlO~2 (mg/kg/day)'1
        4.102X10'1 (mg/kg/day)'1
   500
   19
   10/49
0028d
-61-
07/17/87

-------
calculated from  the  Incidence  of hemanglomas and hemanglosarcomas  1n  female
mice.  The  resulting 1/ED,Q  value was  6.2xlO~2.   Because the  F   factor  1s
<1,   4-chloroanHlne  Is  placed  1n  Potency  Group  3.   An EPA Group C chemical
In Potency Group  3  has  a LOW hazard ranking under CERCLA;  therefore,  the  RQ
based on carc1nogen1c1ty Is 100.
0028d                               -62-                              07/21/87

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                                10.   REFERENCES

ABC  (Analytical  B1o-Chem1stry  Laboratories,  Inc.).   1979a.   Acute  toxlclty
of ACP  to rainbow trout (Salmo qalrdnerl).   U.S.  EPA,  TSCA 8(d) submission.
Doc. No.  878211294, F1che OTS0206222.

ABC  (Analytical  B1o-Chem1stry  Laboratories,  Inc.).   1979b.   Acute  toxlclty
of  ACP  to  fathead  minnows  (Plmephales  promelas).    U.S.   EPA,  TSCA  8(d)
submission, Doc. No. 878211291, Flche OTS0206222.

ABC  (Analytical  B1o-Chem1stry  Laboratories,  Inc.)  1979c.   Dynamic  toxlclty
of  ACP  to  fathead  minnows  (Plmephales  promelas).    U.S.   EPA,  TSCA  8(d)
submission. Doc. No. 878211292, Flche OTS0206222.

ABC  (Analytical  B1o-Chem1stry  Laboratories,  Inc.).   T979d.   Acute'toxlclty
of ACP to Daphnla roaqna.  U.S.  EPA, TSCA 8(d) submission, Doc. No. 878211293,
Flche OTS0206222.

Alexander, M.  and B.K.  Lustlgman.   1966.   Effect  of chemical  structure on
m1crob1ol  degradation  of  substituted  benzenes.   J.  Agrlc.  Food  Chem.   14:
410-413.

Atkinson,  R.   1985.   Kinetics  and  mechanisms  of  the gas-phase  reaction of
the  hydroxyl   radical  with  organic  compound  under   atmospheric  conditions.
Chem. Rev.  85: 69-201.
0028d                               -63-                             07/17/87

-------
Balrd,  R.,  L. Carmona  and  R.L.  Jenkins.   1977.   Behavior  of benzldlne  and
other  aromatic  amines   In aerobic  waste water  treatment.   J.  Water  Pollut.
Control Fed.  49: 1609-1615.

Bartha,  R.    1971.   Fate of  herbicide-derived  chloranlUnes  In  soil.    0.
Agrlc. Food Chem.  19:  385-387.

Boehme, C.  and W.  Crunow.   1969.   Metabolism of carbamate herbicides  1n  the
rat.   I. Metabolism  of  M-chloroan1l1ne  as  a constituent of chlorpropham  and
barban.  Food Cosmet. Toxlcol.   7(2):  125-133.

Bollag,  J.M.,  P.  Blattmann and  T.  Laanlo.   1978.  Adsorption  and  trans-
formation of  four  substituted  anilines   1n  soil.   J.  Agrlc. Food Chem.   26:
1302-1306.
                                           •            *
Bollag, J.M., R.D.  Mlnard  and S.Y. L1u.   1983.  Cross-linkage between  ani-
lines and phenolic humlc constHutents.   Environ.  Sc1. Technol.   17:  72-80.

BMngmann,  G. and  R. Kuehn.   1982.  Results of toxic action of water pollu-
tants on Daphnla magna  straus  tested  by an  Improved standardized  procedure.
Z. Wasser Abwasser Forsch.   15(1):  1-6.

Brooke, L.T., O.J.  Call, O.L. Gelger and  C.E. Northcult, Ed.   1984.  Acute
toxicltles   of  organic   chemicals  to  fathead  minnows  (Plmephales  promales).
Center for  Lake Superior Environmental  Studies, U.  of Wisconsin-Superior.
0028d                               -64-                             07/17/87

-------
 Bulkema,  A.L.,  Jr.,  E.F.  Benfleld and B.R. Nlederlehner.  1982.   Effects  of
 pollution  on   freshwater  Invertebrates.   J.  Water  Pollut.   Control   Fed.
 54(6): 862-868.

 Canter,  O.A.   1985.   Status  of  the National  Toxicology  Program  Carcinogens
 and  Tox1c1ty Studies of p-ChloroanlUne  by  the  Gavage  Route  In F344 Rats and
 B6C3F1 Mice.   Letter  to Lawrence Rosensteln,  Test  Rules  Development  Branch,
 U.S. EPA, Washington, DC.   FYI-OTS-0285-0383 1n Sequence A.

 Chlou, C.T., D.W.  Schmeddlng  and M. Malnes.  1982.  Partitioning  of  organic
 compounds In octanol-water systems.   Environ.  Scl. Techno!.   16: 4-10.

 Cloos, P., A. Moreale, C.  Broers  and  C.  Badot.   1979.   Adsorption and oxida-
 tion  of  aniline  and  p-chloroan1!1ne  by montmorlllonlte.    Chlm.   Organo
 Mlnerale Lab. Phys. Chlm.  Mlnerale  and Catalyse  Grp. Catholic  Univ.  Louvaln,
 Louvaln La Meuve, Belgium.  14: 307-321.

 Coleman,  E.C.,  C. Ho and  S.S.  Chang.   1981.   Isolation and  Identification of
 volatile compounds from baked potatoes.  J.  Agrlc. Food Chem.   29: 42-48.

 Daly. J.W.. G.  Guroff, S.  UdenfMend  and B. WUkop. 1968.   Hydroxylatlon of
 alkyl- and  halogen-substituted   anilines   and   acetanlUdes   by   mlcrosomal
 hydroxylases.  Blochem.  Pharmacol.  17(1): 31-36.

 Dean, J.A., Ed.  1985.  Lange's  Handbook of Chemistry, 13th  ed.  McGraw-Hill
Book Co., New York.   p.  7-200, 10-39.
0028d                               -65-                             07/17/87

-------
Devlllers,  J.,  P.  Chambon,  D.  Zakarya  and M.  Chastrette.   1986.   A  new
approach 1n ecotoxlcologlcal QSAR studies.   Chemosphere.   15(8):  993-1002.

Dunkel,  V.C.,  E.  Zelger,  0.  Bruslck,  et  al.   1985.   Reproduc1b1l1ty  of
mlcroblal mutagenlclty assays: II. Testing  of carcinogens  and  noncardnogens
In  Salmonella  typhlmurlum  and  Escher1ch1a coll.   Environ.  Mutagen.   7(5):
1-248.

E1senre1ch,  S.J.,  B.B. Looney  and J.D.  Thornton.   1981.  Airborne  organic
contaminants of  the Great  Lakes  ecosystem.  Environ.  Sc1. Technol.   15(1):
30-38.

EG&G  Bionomics   Marine Research  Laboratories.   1979.   Tox1c1ty  of  three
materials to embryos  of  eastern oysters (Crassostrea  ylrqlnlca).   U.S.  EPA,
TSCA 8(d) submission,  Doc; Mo. 878211284, F1che  OTS0206222.

El-Dlb,  M.A. and  O.A. Aly.   1976.  Persistence  of some  phenylamlde  pesti-
cides  In the aquatic  environment-Ill.   Biological  degradation.  Water  Res.
10: 1055-1059.

Ellis,  D.D.,  C.M.  Jone,  R.A.  Larson  and  0.3.  Schaeffer.    1982.   Organic
constituents of   mutagenlc   secondary   effluents  from  wastewater  treatment
plants.  Arch.  Environ. Contain. Toxlcol.  11: 373-382.

Fletcher, C.L.  and  O.D. Kaufman.  1980.  Effect  of  sterilization  methods on
3-chloran1l1ne  behavior 1n soil.   J.  Agrlc. Food Chem.   28: 667-671.
0028d                               -66-                             07/17/87

-------
 Freltag,  0.,  I.  Scheunert, W. Klein and  F.  Korte.   1984.   Long-term fate of
 4-chloroan1Hne-14C  1n  soil and plants under  outdoor  conditions.   A contri-
 bution  to terrestrial ecotoxlcology  of  chemicals.   J.  Agrlc.  Food  Chem.   32:
 203-207.

 Freltag,  D.,  L.  Ballhorn,  H.  Geyer  and  F.  Korte.   1985.   Environmental
 hazard  of organic chemicals.  Chemosphere.  14: 1589-1616.

 Fuchsblchler,  G.,  A.  Suess  and  P.  Wallnoefer.   1978.   Degradation  of
 2-chloro-,  3-chloro-2,   4-chloro-2,  3,4-d1chloroan1l1ne  as  well  as  plant-
 absorbed  4-chloroan1l1ne   1n  soil.   Z.   Pflanzenkr.  Pflanzenschutz.   85:
 724-734.

 Furukawa,  T.  and   G.S.   Brlndley.    1973.    Adsorption   and  oxidation  of
 benzldlrie and  aniline by montmorlllonlte  and hectorlte.   21(5): 279-88.   (CA
 80:113092b)

 Garner,  R.C.  and C.A.  Nutman.  1977.  Testing of  some  azo dyes  and their
 reduction  products   for  mutagenlclty  using  Salmonella  tYPhlmurlum  TA1538.
 Mutat. Res.  44(1):  9-19.

 Gattavecchla,  E.,  et  al.   1981.    Effect  of  dlflubenzuron  and   Its  major
 degradation products on  the growth of Euglena  qradlls Z.  and Incorporation
 of glydne-U-14C  1n  protein.   3.  Environ.   Sc1.  Health.   B16:  159.   (Cited
 1n Bulkema et al.,  1982)
0028d                               -67-                             07/17/87

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Gerlke, P. and W.K.  Fischer.  1981.  A  correlation  study,  of  blodegradablllty
determinations  with  various  chemicals  In  various  tests.   II.   Additional
results and conclusions.  Ecotoxlcol.  Environ.  Safety.   5:  45-55.

Geyer, H., G. PolHzkl  and D. Freltago.  1984.   Prediction of  ecotoxlcologl-
cal  behavior  or  chemicals:  Relationship  between  N-octanol/water  partition
coefficient  and  bloaccumulatlon  of  organic  chemicals  by  alga   Chlorella.
Chemosphere.   13: 269-284.

Geyer, H, I. Scheunert  and F. Korte.  1985.  The effects  of  organic environ-
mental  chemicals  on the  growth  of  the  alga  Scenedesmus  subsplcatus:   A
contribution to environmental  biology.   Chemosphere.   14(9):  1355-1370.

Golly, I. and  P. Hlavlca.   1983.   Role of hemoglobin In the  N-ox1dat1on  of
4-chloroan1l1ne.  B1och1m.  Blophys.  Acta.  760(1):  69-76.

Golly, I. and P.  Hlavlca.   1985.   N-Ox1dat1on of 4-chloroan1l1ne  by prosta-
glandln synthase  (EC 1.14.99.1):  Redox cycling of  radical  Intermedlate(s).
Blochem.  J.   226(3): 803-810.

Goodman,  O.G.,  J.H. Ward and  W.D.  Relchardt.   1984.   Splenic flbrosls  and
sarcomas  In F344 rats fed  diets containing  aniline  hydrochloMde,  p-chloro-
anlllne,  azobenzene,  o-tolu1d1ne  hydrochlorlde,  4,4-sulfonyld1anlHne or  0
and C Red No.  9.  J. Natl.  Cancer  Inst.   73(1): 265-274.

Greve,  P.A.  and  R.C.C.  Wegman.    1975.   Determination  and  occurrence  of
aromatic  amines  and their  derivatives  1n  Dutch  surface waters.   Schrlftner.
Ver. Wasser-,  Boden-, Lufthyg.,  Berlln-Dahlem.   46:  59-80.

0028d                               -68-                             07/17/87

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 Gusten,  H.,  L.  Klaslnc  and D.  Marie.   1984.   Prediction  of  the  abiotic
 degradabllHy  of organic  compounds  In the troposphere.  J. Atmos.  Chem.   2:
 83-93.

 Halbach,  U.,  M.  Slebert,  H.  Westermayer  and  C.  Missel.   1983.   Population
 ecology of  rotifers as a  bloassay tool  for ecotoxlcologlcal  tests  In  aquatic
 environments.  Ecotoxlcol. Environ.  Safety.  7(5):  484-513.

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

 Hattorl, M., K. Senoo, S.  Harada, Y.  Ishlzu  and  M'  Goto. * 1984.   The  Daphnla
 reproduction  test  of  some environmental  chemicals.   Seltal  Kagaku.   6(4):
 23-27.

 Hawley,  G.G.   1981.   The  Condensed  Chemical  Dictionary,  10th  ed.   Van
 Nostrand Relnhold Co., New York.  p. 233.

 Hermens, 3.,  P.  Leeuwangh and  A. Musch.  1985.   Joint  toxUHy  of mixtures
 of groups of organic acquatlc pollutants  to  the  guppy  (PoeclHa  retlculata).
 Ecotoxlcol.  Environ. Saf.   9(3): 321-326.

 Howe, R.B. and K.S. Crump.   1982.   GLOBAL  82:  A  computer program to extrapo-
 late  quantal  animal  toxldty   data  to  low  doses.   Prepared  for  Office  of
 Carcinogen Standards.  OSHA, U.S. Oept of Labor under Contract No.  41USC252C3.
0028d                               -69-                             07/17/87

-------
Irmer, U.,  K.  Heuer  and A. Weber.  1985.  Effects of various organic  chemi-
cals  on  the regreenlng of  red  colored Chlorella zof1nglens1s.   Ecotoxlcol.
Environ. Safety.  9(1): 121-133.

Janlcke,  W. and  G.   H1lge.   1980.   Measurement of  the  b1oe!1m1nat1on  of
chloroanlllnes.  Eight papers on  the behavior of  synthetic  organic  compounds
during wastewater treatment.  Gas Hasserfach  Wasser  Abwasser.   121:  131-135.

Julln, A.M.  and H.O.  Sanders.   1978.   Toxlclty  of  IGR, dlbflubenzuron,  to
freshwater  Invertebrates  and fishes.   Mosquito News.   38:  256.   (Cited  1n
Spehar et al.,  1979)

Kaufman, D.D.,  J.R. PUmmer and  U.I. Kl1ngeb1el.  1973.   M1crob1al  oxidation
of 4-chloroan1l1ne.  J. Agrlc.  Food Chem.   21:  127-132.

Kawasaki, M.   1980.    Experiences  with the  test scheme  under   the  chemical
control  law  of  Japan:  An  approach   to  structure-activity  correlations.
Ecotoxlcol.  Environ.  Safety.  4:  444-454.

K1ese, M.   1963.  The  effect of  certain  substltuents  upon the n-ox1dat1on of
aniline .In. vivo.  Arch. Exp. Path. v.  Pharmak.   244:  387-404.

Kllzer,  L.,  I.  Scheunert, H. Geyer, W.  Klein  and F. Korte.   1979.  Labora-
tory  screening  of  the volatilization  rates  of  organic  chemicals  from water
and soil.  Chemosphere.  8: 751-761.
0028d                               -70-                             07/17/87

-------
 King,  E.F.  and  H.A.  Painter.   1983.  Ring-test program  1981-1982.   Assess-
 ment  of b1odegradab1lHy of  chemicals  1n water by  manometrlc  resplrometry.
 Comm.  Eur. Communities. EUR 8631.  31 p.

 Kn1e,  J.,  A.  Haelke,  I.  Juhnke  and W. Schiller.  1983.   Results  of  studies
 of  chemical  substances  using  four  blotests.   Dtsch.  Gewaesserkd.  M1tt.
 27(3):  77-79.

 Kondo,  H.   1978.   Simulation studies  of  degradation  of  chemicals  In  the
 environment: Simulation studies of  degradation  of chemicals  1n  the water  and
 soil.   Environment Agency, Office of Health Studies,  Japan.

 Kool,  H.J., C.F.  Van  Kreljl  and 8.C.J. Zoeteman.  1982.   Toxicology  assess-
 ment of organic  compounds 1n  drinking  water.   Cr1t. Rev.  Environ.  Control.
 12: 307-357.

 Korte,   P.,  0.  Freltag,  H.  Geyer,  W.  Klein, A.G. Kraus  and E.  Lahan1at1s.
 1978.   Ecotox1colog1c  profile  analysis:  A concept for  establishing ecotoxl-
 cologlcal priority list for  chemicals.   Chemosphere.   1: 79-102.

 KouMs.  C.S.  and  J.  Northcott.   1963.   Aniline.   In:  K1rk-0thmer  Encyclo-
 pedia  of Chemical  Technology,  2nd  ed., Vol.  2, A.  Standen,  Ed.   John  Wiley
and Sons, Inc.,  New York.   p.  423-424.

 Kuney,   J.H.,  Ed.   1985.   Chemcyclopedla  1986, Vol.  4.   American  Chemical
Society, Washington, DC.
0028d                               -71-                             07/17/87

-------
Kussmaul,  H.    1978.   Behavior  of  Persistent  Organic  Compounds  1n  Bank-
filtrated Rhine Water.  Pergamon Press,  CITY,  STATE?   p.  265-275.

Lelfer, Z., 0. Hyman  and H.S. Rosenkranz.   1981.   Determination of  genotoxlc
activity using  DMA  polymerase-defldent and proficient  E_. coll.   Short-term
Tests Chem. Cardnog.   p.  127-139.

Lenk, W. and  H. Sterzl.   1981.  Effect  of  an additional chloride atom  1n  3
position on   the  blotransformatlon .In.  vitro  of 4-chloroprop1onan1l1de  and
4-chloroan1l1ne  and  on  the  formation  of   ferrl  hemoglobin.   22nd  Spring
Meeting of the  Deutsche Pharmakologlsche Gesellschaft  (German  Pharmacologi-
cal Society), Mainz,  West  Germany, March 10-13.   Naunyn-Schmledeberg's  Arch
Pharmacol.   p. 316.   (Suppl.)

Lucas,  S.V.   1984.    GC/MS analysis of  organlcs  In  drinking water  concen-
trates  and advanced waste  treatment concentrates.  Vol.  2.  Computer-printed
tabulations  of   compound   Identification results  for  large-volume  concen-
trates.  EPA  600/1-84-020B.   NTIS  PB85-128239.   Columbus Labs.  Health  Eff.
Res. Lab.,  Columbus, OH.  p.  397.

Lyman,  W.J.,  W.F.   Reehl and  D.H.   Rosenblatt.   1982.   Handbook  of  Chemical
Property Estimation  Methods.    McGraw  H111  Book  Co..   New York.   p. 5-5,
15-13, 15-21,  15-27.

Lyons,  C.D.,  S.E.  Katz and  R. Bartha.    1985.   Persistence and  mutagenlc
potential  of   herbicide-derived  aniline  residues  1n  pond  water.   Bull.
Environ. Contain. Toxlcol.   35: 696-703.
0028d                               -72-                             07/17/87

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 Lysak,  A.  and  J. Mardnek.   1972.   Multiple  toxic  effect  of  simultaneous
 action  of  some  chemical  substances  on  fish.   Rooz.  Nauk Roln.  Ser.  H
 Rybactlvo.  94(3): 53-63.

 Malaney,  G.W.   1960.   Ox1dat1ve  abilities  of  aniline-acclimated  activated
 sludge.   J. Water Pollut. Control Fed.  32: 1300-1311.

 Maronpot,  R.R.,  M.B.  Shlmkln,  H.P.  WHschl,   L.H.  Smith  and  J.M.  CUne.
 1986.   Strain A mouse pulmonary  tumor  test result for  chemicals  previously
 tested  1n  the  National   Cancer  Institute  carc1nogen1c1ty  tests.    J.  Natl.
 Cancer  Inst.  76(6): 1101-1112.

 Maule,  A.  and  S.J.L.  Wright.   1983.  Physiological  effects  of  chlorpropham
 and 3-chloroan1l1ne on some  cyanobacterla  and  a green alga.   Pestle Blochem.
 PhysVol.  19(2): 196-20?.

 Maule,  A.  and  S.J.L.  Wright.   1984.   Herbicide  effects  on  the  population
 growth  of  some  green algae  and  cyanobacterla.   J. Appl.  Bacterlol.   57(2):
 369-379.

McGregor,   0.,  R.O.  Prentice.  M.  McConvllle,   Y.J.  Lee  and W.J.  Caspary.
 1984.   Reduced  mutant  yield  at  high  doses  In  the  Salmonella  activation
assay: The cause 1s not always toxldty.   Environ. Mutagen.  6(4):  545-558.

McLean,  S., G.A.  Starmer and  J.  Thomas.   1969.   Methemoglobln  formation by
aromatic amines.  J.  Pharm.  Pharmacol.  21(7):  441-450.
0028d                               -73-                             07/17/87

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McLeese,  O.H.,  V.   ZHko  and  M.R.  Peterson.   1979.    Structure-lethality
relationships  for  phenols,  anilines and  other  aromatic  compounds In  shrimp
and clams.  Chemosphere.   8(2):  53-57.

Means,  J.C.    1983.   Affinity  of  selected aromatic  amines  for dissolved
organic carbon  In  subsurface waters.   In.:  Am.  Chem.  Soc.  186th Natl. Mtg.
Washington,  DC,  28  Aug  -  2  Sept. 83.   Preprints.  Dlv.  Environ. Chem.   23:
250-251.

Miller, G.C.  and D.G.  Crosby.   1983.  Photoox1dat1on of  4-chloroan1l1ne  and
N-(4-chlorophenyl)   benzene  sulfonamlde  to  nltroso- and   nitro-products.
Chemosphere.   12:  1217-1228.

Mlnard. R.O.,  S. Russel  and  J.M.  Bollag.  1977.  Chemical  transformation of
4-chloroan1T1ne to a trlazene In  a. bacterial culture medium.   J.  Agrlc.  Food
Chem.  25: 841-844.

Morrison,   R.T.  and  R.N. Boyd.   1966.    ElectrophHlc aromatic  substitution.
In.: Organic Chemistry,  2nd ed.   Allyn and Bacon,  Inc.,  Boston, MA.  p.  346.

Morrison,  R.T. and  R.N.  Boyd.   1973.  Organic Chemistry, 3rd ed.  Allyn  and
Bacon, Inc.,  Boston, MA.

NCI  (National Cancer  Institute).   1979.   Bloassay  of   p-Chloroan1l1ne  for
Possible  Cardnogenldty.    NCI  Carclnogenesls   Tech.  Rep.  Ser.  No.  189.
[Also publ. as DHHS (NIH) 79-1745].  NTIS PB 295896.
0028d                               -74-                             07/17/87

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 NIOSH   (National  Institute  for  Occupational  Safety  and  Health).   1984.
 Current  Awareness  File.   RTECS  {Registry  of  Toxic  Effects  of  Chemical
 Substances).  Cincinnati, OH.

 Nomura,  A.   1975.   Sulfhemoglobln  formation  by  various  drugs.   Nippon
 YakuMgaku Zasshl.  71(4): 351-365.

 Nomura, A.   1980.  Studies of  sulfhemoglobin  formation  by various  drugs (4).
 Influences  of  various  antidotes   on   chemically  Induced  methemogloblnemla
 (author's transl).  Nippon Yakurlgaku Zasshl.   76(6): 435-446.

 Northcott,  J.   1978.   Amines,  aromatic.   Ln:  Klrk-Othmer  Encyclopedia  of
 Chemical Technology,  3rd ed.,  Vol.  2,  M.  Grayson and  0.  Eckroth,  Ed.   John
 Wiley and Sons, New York.  p. 318.

 NTP  (National Toxicology  Program).  1983.   Short-term jn. vitro mammalian cell
 assay results.  NTP Tech. Bull.  9: 7.

 NTP  (National  Toxicology Program).  1987.   Toxicology Research  and Testing
 Program.  Management Status Report.  1/13/87.

 Pa1,  V.,   S.F.  Bloorofleld   and   J.H.  Gorrod.    1985.    Mutagenlclty  of
N-hydroxylam1nes and N-hydroxycarbamates  towards  strains  of Escherlchla coll
and Salmonella typhlrourlum.  Mutat. Res.  151(2): 201-207.

Pan,  H.P.,   J.R.  Facts   and   T.R.  Oevereux.    1979.    Hepatic  mlcrosomal
N-hydroxylatlon   of   p-chloroan1!1ne    and    p-chloro-N-methylan1!1ne   In
red-winged blackbird compared with  rat.  Xenoblotlcs.  9(7): 441-446.

0028d                               -75-                             07/17/87

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Parrls,  G.E.   1980.  Covalent  binding of  aromatic  amines  to  humates.  1.
Reactions  with   carbonyls   and  qulnones.    Environ.   Sc1.  Techno!.   14:
1099-1105.

Parrls,  G.E.,  G.W.  Dlachenko,   R.C.  Entz,  J.A.  Popp1t1  and  P.  Lombardo.
1980.   Waterborne  methylene  b1s(2-chloranH1ne)  and 2-chloranHlne contami-
nation around Adrian, HI.   Bull. Environ.  Contain.  Toxlcol.   24:  497-503.

Perrln,  D.O.   1972.   Dissociation constants  of  organic   bases  In   aqueous
solution.   IUPAC  chemical   data   series.   Supplement  1972.   Buttersworth,
London.

Placente, V., P. Scardala, C. Ferro and R.  Glgll.   1985.   Vaporization  study
of o-,  m-,  and  p-chloroanlllne  by torsion-weighting effusion vapor pressure
measurements.  J. Chetn.  Eng.  Data.   30:  372-376.

Plenta,  R.J.    1980.   Transformation  of  Syrian  hamster  embryo cells  by
diverse  chemicals  and  correlation  with  their  reported  carcinogenic and
mutagenlc activities.   Chem. Hutagens.  Prln.  Methods  their Detection.  6:
175-202.

Plenta,  R.J.  and  J.C.  Kawalek.   1981.   Transformation  of hamster embryo
cells by aromatic amines.   Natl. Cancer Inst.  Monogr.   58:  243-251.

PHter,  P.   1976.   Determination  of  biological  degradablHty  of   organic
substances.   Hater Res.   10:  231-235.
0028d                               -76-                             07/17/87

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 Polrler,  L.A.  and  P.O.  Oe Serres.  1979.  Initial  National  Cancer  Institute
 studies on mutagenesls as a prescreen for chemical carcinogens:  An appraisal.
 J. Natl.  Cancer Inst.  62(4): 919-926.

 Prasad,  I.   1970.   Mutagenlc  effects of  the herbicide  3',  4'-Olchloropro-
 p1onan1!1de and Its degradation products.  Can. 0. H1crob1ol.  16: 369-372.

 Rankln, G.O.,  D.J.  Yang,  K.  Cressey-Venezlano, S.  Casto,  R.T.  Wang and  P.I.
 Brown.   1986.   in.  vivo  and  in  vitro  nephrotoxldty  of  aniline  and  Its
 monochlorophenyl derivatives  In  the  Fischer  344 rat.   Toxicology.   38(3):
 269-284.

 Reber,  H.,  V.  Helm and  G.K.   Kararth.   1979.   Comparative  studies on  the
 metabolism  of  aniline and  chloranHlnes  by  Pseudomonas  multlvorans  strain
 AN 1.  Eur.  J.  Appl. M1crob1ol. Blotechnol.  7: 181-189.

 Rlppen, G.t  M.  Ilgensteln, W.  Kloepffer  and  H.J.  Poremskl.  1982.  Screening
 of  the  adsorption  behavior   of   new chemicals:   Natural  soils  and  model
 adsorbents.   Ecotoxlcol.  Environ. Safety.  6(3):  236-245.

 Rosenkranz.  H.S.  and L.A.  Polrler.  1979.   Evaluation of  the  mutagenldty
 and  DNA-mod1fy1ng  activity of  carcinogens and  noncardnogens   In  mlcroblal
 systems.  J. Natl.  Cancer Inst.  62(4):  873-892.

 Rump,  H.H.    1984.   Behavior   of  some  organic  mlcropollutants  In  river
 sediments and  groundwater.  Fresenlus Z.  Anal. Chem.  319: 165-171.
0028d                               -77-                             07/17/87

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Sadtler  Research  Laboratory.   1960a.  Standard  UV  Spectra No. 376.   Phila-
delphia, PA.

Sadtler  Research  Laboratory.   1960b.  Standard  UV  Spectra No. 393.   Phila-
delphia, PA.

Sadtler  Research  Laboratory.   1962.   Standard UV  Spectra No. 254.   Phila-
delphia, PA.

Schauerte,  W.,  J.P.  Lay,  W.  Klein and F.  Korte.   1982.  Long-term  fate  of
organochlorlne  xenoblotlcs  1n  aquatic   ecosystems.    Ecotoxlcol.   Environ.
Safety.  6: 560-569.

Schmidt-Sleek,  P.,  W.  Haberland.  A.W. Klein  and  S.  Caroll.   1982.   Steps
towards environmental hazard assessment of  new chemicals (Including  a hazard
ranking scheme, based upon directive 79/831/EEC).  Chemosphere.  11:  383-415.

Shelton D.R.  and  J.M.  Tledje.   1981.  Development  of Tests for  Determining
Anaerobic  B1odegradat1on  Potential.   Michigan State University.  Department
Crop  Soil.   Sc1.,   East   Lansing,   HI.    p.  92.    EPA   560/5-81-013.   NTIS
P884-166495.

Simmon, V.F.   1979a.  In.  vitro  mutagenldty  assays  of  chemical  carcinogens
and  related compounds  with  Salmonella typhlmurlum.   J.  Natl. Cancer  Inst.
62(4): 893-899.
0028d                               -78-                             07/17/87

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 Simmon,  V.F.   1979b.   I.n  vitro assays for recomblnogenlc activity  of  chemi-
 cal  carcinogens  and related compounds with Saccharomyces cerevlslae 03.   J.
 Natl. Cancer Inst.  62(4): 901-910.

 Smyth,  H.F.,  C.P.  Carpenter  and  C.S.  Well.   1962.   Range-finding  toxIcHy
 data: List VL.  Am. Ind. Hyg. Assoc. 0.  23:  95-107.

 Society  of Dyers  and  ColoMsts.   1971.   Colour  Index,  3rd  ed.,  Vol.  4,
 p. 4700.  Published by The Society of Dyers and ColoMsts,  Great Britain.

 Spehar,  R.L.,  G.U. Hoicombe,  R.W. Carlson,  R.A.  Drummond,  J.D. Yount  and
 Q.H.  Pickering.   1979.   Effects of pollution  on freshwater fish.   J.  Hater
 Pollut. Control Fed.  51(6): 1616-1694.

 SRI   (Stanford  Research  Institute).    1986.    1986  Directory  of  Chemical
 Producers:  United  States  of America.   SRI  International,  Menlo Park,  CA.
 p. 549.

 Suess,  A.   1973.   Application  of  radlotracers 1n  studying  the persistence,
 sorptlon and degradation of herbicides  1n  soil.   Part  of coordinated program
on Isotope-tracer  aided  studies of the  origin and fate of  foreign  chemical
 residues 1n the agricultural environment.  Nucl.  Sc1.  Bstr.   30: 21155.

Suess,  A.,  G.  Fuchsblchler and  C.  Eben.   1978.   Degradation  of  aniline,
4-chloroan1l1ne and 3,4-d1chloroan1l1ne  In  various  soils.   Z.  Pflanzezer-
naehr. Boden kd.  141:  57-66.
0028d                               -79-                             07/17/87

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Surovtseva,  E.G.,  G.K.  Vaslleva,  A.I.  Volnova and  Yu.V.  Shurukhln.  1977.
Acetylatlon  of  aniline and  Us  chloro-substHuted  analogs  by a Pseudomonas
aurantlaca culture.  Dokl. Akad.  Nauk.  SSSR.   237:  220-223.   (CA 88:18853g)

Thorn,  N.S.  and  A.R.  Agg.   1975.   The  breakdown of  synthetic  organic com-
pounds 1n biological processes.   Proc.  R.  Soc.  Lond.  B.   189:  347-357.

Thompson, C.Z.,  L.E.  H111,  J.K.  Epp and  G.S.  Probst.  1983.  The  Induction
of  bacterial mutation and  heatocyte  unscheduled   ONA  synthesis  by mono-
substituted anilines.  Environ. Hutagen.   5(6):  803-811.

Topham,  J.C.   1979.  The detection  of  carcinogen-Induced  sperm head  abnor-
malities In mice.  Mutat. Res.  69: 149-155.

Traul, K.A.,  K. Takayama,  V.  Kachevsky,  R.J.  Hlnk  and  J.S. Wolff.  1981.
Rapid In vitro assay for  cardnogenldty of chemical  substances 1n  mammalian
cells  utilizing  an attachment-Independence endpolnt.   2.  Assay validation.
J. Appl.  Toxlcol.  1(3):  190-195.

Uehleke,   H.   1967.   Stimulation  of  several  mlcrosomal  drug oxidations  by
phenobarbltal, methylcholanthrene  and chlorophenothane,  singly and  1n combi-
nations.   Naunyn-Schmledeberg's Arch. Pharmakol. Exp. Pathol.   259(1): 66-90.

Uehleke,  H.,  0.  Reiner  and  K.H.  Hellmer.  1971.   Perinatal development  of
tertiary amlne  N-ox1dat1on  and  NAOPH cytochrome  C  reduction  1n   rat  liver
mlcrosomes.   Res. Commun. Chem.  Pathol.  Pharmacol.   2(6): 793-805.
0028d                               -80-                             07/17/87

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 U.S.  EPA.   1980.   Guidelines and  Methodology Used  In  the  Preparation  of
 Health  Effect  Assessment  Chapters   of   the   Consent  Decree  Water  Quality
 Criteria  Documents.  Federal Register.  45(231): 49347-49357.

 U.S.  EPA.  1983.   Methodology and Guidelines  for  Reportable  Quantity  Deter-
 minations  Based on  Chronic  Toxldty  Data.  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,
 Washington, DC.

 U.S.  EPA.   1984.   Aniline and  Chloro-,  Bromo-  and/or  NHroanlUnes; Response
 to the Interagency Testing Committee.   Federal  Register.   49:  108-126.

 U.S.  EPA.   1986a.   Methodology for  Evaluating  Cardnogenldty  In Support  of
 Reportable Quantity Adjustments Pursuant  to CERCLA Section 102.   Prepared  by
 the  Office of Health  and Environmental   Assessment,  Washington,  DC for  the
 Office of Solid Waste and Emergency  Response,  Washington, DC.

 U.S.  EPA.   1986b.    Guidelines   for  Carcinogen   Risk  Assessment.    Federal
 Register.  51: 33992-34003..

 U.S.  EPA.    1987a.    SANSS  (Structure  and   Nomenclature   Search  System)
 database.  On-line.

U.S.  EPA.   1987b.   Graphical  Exposure  Modeling  System  (GEMS).   Fate  of
Atmospheric Pollutants (FAP).   Office  of  Toxic  Substances, Washington,  DC.
0028d                               -81-                             07/17/87

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USITC  (U.S.  International Trade  Commission).   1984.   Imports  of  Benzenold
Chemicals and Products.  1983.  USITC Publ.  1548,  Washington,  DC.

Van  Blade!,  R.  and  A.   Moreale.   1977.   Adsorption  of  herbicide  derived
p-chloroanlUne residues  1n  soils  and a  predictive  equation.  J. Soil  Scl.
28: 93-102.

Vasllenko, N.M.  and  V.I.  Zvezdal.   1972.   Comparative  evaluation of  blood
changes  In acute  and  subacute poisoning  with  aromatic  nltro- and  ami no-
compounds.  Farmakol. Tokslkol.  (Moscow).  35(1):  108-110.

Vasllenko, N.H.,  V.I. Zvenzdal  and  I.I.  Kovalenko.   1972.   Inactlvatlon  of
the blood  respiratory pigment under the  effect  of aromatic  nltro and  amlno
compounds  from  the  benzene series.   Sovrem. Probl. Blokhlm.  Oykhanlya  KUn.
Mater. Vses.  Konf.  2(1): 411-413.

Verschueren,  K.  1983.   Handbook of  Environmental  Data  on  Organic Chemicals.
2nd ed.  Van  Nostrand Relnhold Co.,  New York.  p.  355-357.

Ward,  J.M. and G. Reznlk.  1981.  Nonhematopoletlc sex  dependent  sarcomas  of
the spleen Induced by  6  aromatic amines  or  derivatives  and their  association
with  splenic  flbrosls and methemogloblnemla.   Proc.  Am.  Assoc.  Cancer  Res.
Am. Soc. Cl1n.  Oncol.  22(0): 74.

Ward,  J.M., G.  Reznlk and P.M.  Garner.   1980.  Prollferatlve lesions of the
spleen In male F344  rats  fed  diets  containing  p-chloroanlUne.   Vet.  Pathol.
17(2): 200-205.


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 Uegman,  R.C.C.  and  G.A.L.  Oekorte.   1981.   Aromatic  amines  1n  surface  waters
 of  the Netherlands.  Water Res.  15: 391-394.

 Williams,  G.M., M.F.  Laspla  and  V.C.  Dunkel.   1982.   Reliability  of  the
 hepatocyte  primary  culture/DNA,  repair test In testing of  coded  carcinogens
 and  noncardnogens.  Mutat. Res.  97: 359-370.

 Wlndholz,  M.,  Ed.   1983.   The Merck Index, 10th  ed.   Merck and  Co.,  Inc.,
 Rah way,  NJ.  p. 297.

 Worobey,  B.L.   and  G.R.8.  Webster.   1982.   Hydrolytlc  release  of  tightly
 complexed  4-chloroan1l1ne  from  soil  humlc  add:  An analytical method.   J.
 Agrlc. Food Chem.  30: 161-164.
                                                 •
 Yoshloka, Y., Y. Ose and T.  Sato.   1985.   Testing  for  the tox1c1ty of  chemi-
 cals with Tetrahymena pyrlformls.  Sc1. Total Environ.   43(1-2): 149-157.
        E.,  B.  Anderson,  S.  Haworth, T. Lawlor,  K.  Mortelmans  and  W.  Speck.
1987.   Salmonella  mutagenlcHy  tests.   Results  from  the   testing  of  255
chemicals.  Environ. Mutagen.  9: 1-29.

Zepp, R.G.  and  P.P. Schlotzhauer.   1983.   Influence of algae  on  photolysis
rates of chemicals 1n water.   Environ. Sc1.  Technol.   17: 462-468.

Zeyer, J. and P.C.  Kearney.   1982.   Mlcroblal  degradation  of para-chloroanl-
Une  as  sole carbon  and nitrogen  source.   Pestle.  Blochem.  Physlol.   17:
215-223.
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Zlmmer,  D.,   J.  Mazurek,  G.  Petzold  and  E.K.  Bhuyan.   1980.    Bacterial
mutagenlcUy and mammalian  cell  DNA damage by several  substituted  anilines.
Mutat. Res.  77(4): 317-326.

Zoeteman, B.C.J.,  K.  Harmsen,  J.B.H.J.  Llnders,  C.F.H. Horra and U.  Slooff.
1980.  Persistent  organic  pollutants  In river water  and groundwater of  the
Netherlands.   Chemosphere.   9:  231-249.

Zvezdal,  V.I.   1972.   Comparative  diagnostic  value of  various  pathological
derivatives of  hemoglobin  In conditions of acute  and  subacute poisoning  by
aniline,  nitrobenzene  and   their  chloride  derivatives.  Farmakol.  Tokslkol.
7: 159-162.
0028d                               -84-                             07/17/87

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                                  APPENDIX A

                              LITERATURE SEARCHED



     This  HEED   Is  based  on  data  Identified  by  computerized  literature

 searches of the  following:


         TSCATS
         CASR online (U.S. EPA Chemical Activities Status Report)
         TOXLINE
         TOXBACK 76
         TOXBACK 65
         RTECS
         OHM TADS
         STORET
         SRC Environmental Fate Data Bases
         SANSS
         AQUIRE
         TSCAPP
         NTIS
         Federal Register


These searches were  conducted In January, 1987.   In  addition,  hand searches

were made of  Chemical  Abstracts  (Collective Indices  5-9),  and  the following

secondary sources should be reviewed:


    ACGIH (American  Conference of  Governmental  Industrial  Hyg1en1sts).
    1986.  Documentation  of   the  Threshold  Limit  Values  and Biological
    Exposure Indices, 5th ed.  Cincinnati, OH.

    ACGIH (American  Conference of  Governmental  Industrial  Hyglenlsts).
    1986-1987.  TLVs: Threshold  L1mH  Values  for Chemical Substances In
    the  Work  Environment  adopted  by  ACGIH with  Intended  Changes  for
    1986-1987.  Cincinnati, OH.  Ill p.

    Clayton,   G.D.  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.  2B.   John Wiley  and
    Sons, NY.   p. 2879-3816.

    Clayton,   G.D.  and  F.E.  Clayton,  Ed.   1982.   Patty's  Industrial
    Hygiene  and  Toxicology,  3rd rev.  ed., Vol.  2C.   John Wiley  and
    Sons, NY.   p. 3817-5112.
0028d                               -85-                             07/17/87

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    Grayson, M.  and 0.  Eckroth,  Ed.   1978-1984.  K1rk-0thmer  Encyclo-
    pedia of Chemical Technology, 3rd ed.  John WHey 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.   WHO, IARC, Lyons,  France.

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

    NTP  (National Toxicology  Program).   1986.  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).   1986.   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   1n
    Programs.   Registration  Standards   and  the Data  Call 1n  Programs.
    Office of Pesticide Programs,  Washington, DC.

    U.S.  EPA.   1985.  CSB Existing Chemical  Assessment Tracking System.
    Name  and CAS Number Ordered  Indexes.  Office of Toxic  Substances,
    Washington.  DC.

    USITC  (U.S.  International  Trade   Commission).    1985.    Synthetic
    Organic  Chemicals.   U.S.  Production  and Sales,  1984, USITC  Publ.
    1422, 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.
0028d                               -86-                             07/17/87

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     In  addition,  approximately  30 compendia  of  aquatic toxldty  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  Toxldty
     of  Chemicals  to  F1sh  and  Aquatic   Invertebrates.   Summaries  of
     Toxldty  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.
0028d                               -87-                             07/17/87

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                                  APPENDIX B
                    Cancer Data Sheet for Derivation of q-j*
Compound:  4-Chloroan1l1ne
Reference:  NCI, 1979
Specles/straln/sex:  rat, F344, M
Route/vehicle:  oral, diet
Length of exposure (1e) = 78 (weeks)
Length of experiment (Le) * 102 (weeks)
Llfespan of animal (L) * 104 (weeks)
Body weight » 0.38 kg (measured)
Tumor site and type:  spleen and spleen capsule,  fibroma,  flbrosarcoma,
                      hemanglosarcoma, osteosarcoma or  sarcoma  NOS
Experimental Doses
or Exposure (ppm)
0
250
500
Transformed Dose
(mg/kg/day)
0
9.6
19.1
Incidence
No. Responding/No.
0/20
0/49
10/49
Tested

Unadjusted q-|* - 5.78215x10'" (mg/kg/day)'1
Human q-j* « 3.48733x10"* (mg/kg/day)'1
                                       U.S. Environmental Protection Agency
                                       Region V,  Library
                                       230 South Dearborn Street
0028d                                -aa^hicago, Illinois  60604         07/17/87

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                              APPENDIX B  (cont.)

                    Cancer Data Sheet for Derivation of q-j*
Compound:  4-Chloroanlllne

Reference:  NCI, 1979

Specles/straln/sex:  mouse, B6C3F1, F

Route/vehicle:  oral, diet

Length of exposure (le) = 78 (weeks)

Length of experiment (Le) - 91 (weeks)

Llfespan of animal (L) = 91 (weeks)

Body weight = 0.028 kg (measured)

Tumor site and type:  hemanglosarcoma or hemangloma, all sites
Experimental Doses  Transformed Dose
      (ppm)            (mg/kg/day)
            Equivalent
            Human Dose          Incidence
            (mg/kg/day)  No. Responding/No. Tested
         0
      2500
      5000
  0
279
557
 0
20.6
41.1
0/18
3/49
8/42
Human q-|* = 6.5xlO"» (mg/kg/day)"1
0028d
         -89-
                          07/21/87

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