United Ststes
            Environmental Protection                              ECAO-CIN-P223
            Agency                                       June, 19Q7
EPA      Research  and
            Development
             HEALTH AND ENVIRONMENTAL EFFECTS PROFILE
             FOR 3,3'-DIMETHYLBENZIDINE
            Prepared for
            OFFICE OF SOLID WASTE AND
            EMERGENCY RESPONSE
            D         . .
            Prepared by        230 south 0**™ street
                                    Chicago, |/iino;s 60604
            Environmental Criteria and Assessment  Office
            Office of Health and Environmental Assessment
            U.S. Environmental Protection Agency
            Cincinnati, OH  45268
                        DRAFT:  DO NOT CITE OR QUOTE


                                NOTICE

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

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                                  DISCLAIMER

    This report  1s  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  Profiles  (HEEPs) are  prepared  for the
Office  of  Solid Waste  and  Emergency  Response  by  the Office of  Health and
Environmental  Assessment.    The  HEEPs  are  Intended  to  support  listings  of
hazardous constituents  of  a wide  range  of  waste  streams  under  Section 3001
of the  Resource  Conservation and Recovery Act  (RCRA), as  well  as to provide
health-related limits for  emergency actions under  Section  101  of the Compre-
hensive  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   and   the  dates  of  the  searches  are  Included  1n  the
section  titled  "Appendix:  Literature  Searched."   The  literature  search
material Is current through November,  1985.

    Quantitative  estimates  are   presented   provided  sufficient  data  are
available.  For systemic toxicants, these Include  Reference  doses (RfDs) for
chronic exposures.   An  RfD  1s defined as the amount of a chemical  to  which
humans  can  be  exposed  on a dally  basis  over  an  extended period  of  time
(usually a  lifetime) without suffering a deleterious effect.  In the case of
suspected  carcinogens,  RfDs are  not  estimated  In  this   document  series.
Instead, a  carcinogenic potency  factor  of  q-j*  1s  provided.  These  potency
estimates are derived for  both oral and  Inhalation exposures where possible.-
In addition,  unit  risk estimates  for  air and  drinking water are presented
based on Inhalation and  oral data, respectively.

    Reportable quantities  (RQs)  based  on both chronic toxldty  and cardno-
genlclty are derived.  The  RQ Is  used  to determine the quantity'of a hazard-
ous substance  for  which notification  1s required  1n the event  of  a  release
as specified under CERCLA.  These two RQs (chronic  toxldty and carclnogen-
1c1ty)  represent  two of  six scores  developed   (the remaining  four  reflect
1gn1tab1l1ty, reactivity,  aquatic toxldty and acute mammalian toxldty).

    The  first  draft  of  this  document  was   prepared by  Syracuse  Research
Corporation  under  EPA  Contract  Mo.   68-03-3228.   The document was  subse-
quently  revised  after  reviews   by staff within  the Office  of Health  and
Environmental Assessment:  Carcinogen  Assessment Group, Reproductive  Effects
Assessment Group,  Exposure Assessment  Group,  and  the Environmental  Criteria
and Assessment Office 1n Cincinnati.

    The HEEPs will  become  part of the  EPA RCRA and  CERCLA  dockets.
                                      111

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                               EXECUTIVE  SUMMARY

    3,3'-D1methylbenz1d1ne  1s  a  white  to  reddish  crystalline compound  at
ambient  temperature.   It  Is  sparingly  soluble  In water  and  1s  soluble  1n
ether,  alcohol  and dilute  adds  (Wlndholz,  1983).   It 1s  a weak  base  and
undergoes  reactions   similar   to  those  of   benzldlne   (IARC,   1972;  Ferber,
1978).   3,3'-01methylbenz1d1ne 1s  made  by  the  reaction  of  o-n1trotoluene
with zinc dust and caustic  soda to  form  hydrazotoluene,  which 1s subsequent-
ly  rearranged  by boiling  with sulfurlc  or  hydrochloric acid  (Lurle,  1964;
Powell et al., 1979).  No  current commercial  manufacturers  of 3,3'-d1methyl-
benzldlne 1n the  United  States were reported 1n  SRI  (1986)  or  USITC (1985).
In  1983, 75,307  pounds  of  this compound  was  Imported  Into  the  United States
through  principal  customs  districts   (USITC,  1984).   It  Is estimated  that
>75X of  the 3,3'-d1methylbenz1d1ne consumed  Is  used  as an  Intermediate  1n
the production  of azo dyes  and pigments used  for coloring  paper,  textiles
and  leathers  and  for  diverse  applications   1n   the   petroleum,   rubber,
plastics, wood,  soap,  fur and  hair   dye Industries   (Powell  et al.,  1979;
NIOSH,  1980).    Approximately   20%  of  the  3,3'-d1methylbenz1d1ne  consumed
domestically 1s  used  1n the production  of  polyurethane-based  high  strength
elastomers,  coatings and rigid plastics  and <5X 1s used for chlorine detec-
tion and other  laboratory procedures (Powell  et  al.,  1979).
    3,3'-D1methylbenz1d1ne 1s a weak base and as  such, may  be protonated and
form salts  that  are more  soluble  than  the  parent compound.   Variations  In
the behavior  of  3,3'-d1methylbenz1d1ne  1n  the  environment  may result  from
protonatlon.  If released  to water, 3,3'-d1methylbenz1d1ne  Is  expected  to  be
oxidized by  Fe{*3)  and  other  cations  fairly  rapidly  (U.S.  EPA, 1979).   The
half-life of this  oxidation may be <4 hours.   It 1s  likely  to be resistant
                                      1v

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to  hydrolysis  (Schmltz  and Rooze,  1981;  Lyman  et  al.,  1982).   Potential
exists for  significant  photolysis of  3,3'-d1methylbenz1d1ne.   Adsorption to
mlcrocrystalUne clay and covalent binding  to  suspended  solids  and sediments
may be  significant  (U.S. EPA, 1979;  ParMs,  1980).  In fact,  adsorption by
mlcrocrystalUne clays may be the most  Important  process  1n  water.  Bloaccu-
mulatlon  1n  aquatic organisms and  volatilization  from  water  should not  be
significant  removal  processes.    If  released  to  air,  vapor phase  3,3'-d1-
methylbenzldlne  1s  predicted to react  with  hydroxyl  radicals  and  has  an
estimated half-life of 4.0 hours  at  25°C  (U.S.  EPA, 1986b).   Direct photoly-
sis In the troposphere Is also likely  to  be a  significant  removal mechanism.
Reaction  with  ozone  Is  unlikely (U.S.  EPA,  1986b).   If  released to  soil,
3,3'-d1methylbenz1d1ne Is  likely to be  resistant   to  hydrolysis  (Lyman  et
al.,  1982).   3,3'-01methylbenz1d1ne  may  be  Immobilized  1n  soil  by  physical
adsorption  and covalent  binding.   Some  mobilization  may  occur In  acidic
                                              *
soils because  of  the protonatlon process.   Volatilization from wet  and  dry
soil  surfaces  should  not   be   significant.    Soil-catalyzed   oxidation   of
3,3'-d1methylbenz1d1ne may be the most  significant  reaction  of  this  chemical
and the  half-life  of this reaction  may be <1  day  (U.S.  EPA,   1980;  Lapp et
al., 1981).
    Monitoring data regarding 3,3'-d1methylbenz1d1ne could not  be located In
the available  literature as  cited   In  the Appendix.  This  compound 1s  not
known to  occur naturally  1n the environment   (U.S.  EPA,  1980).   Potential
sources  of • major -release  are In  air-borne partlculate matter and wastewater
from manufacturing and processing plants  for  dyes  and pigments  derived  frpm
3,3'-d1methylbenz1d1ne (U.S.  EPA, 1980;  Lapp et al., 1981).
    Minor  sources  of release  may  originate  from  clothing, colored  paper,
textiles, leather and other  dyed materials  that are commonly disposed  of In
solid waste disposal sites (U.S.  EPA, 1980).

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     The workers who  manufacture and handle 3,3'-d1methylbenz1d1ne-based dyes
 and  pigments  are  likely  to be  the most  exposed  segment  of  the population
 (U.S.  EPA, 1980)i."  Urine  samples  from  some  workers  exposed  to  azo  dyes
 during manufacture  (two  sites)  and use  (four  sites)  contained ppb levels of
 3,3'-d1methylbenz1d1ne  (Lowry   et  al.,  1980).  Workers  In  biochemical  and
 clinical  laboratories  where  3,3'-d1methylbenz1d1ne  1s  used may  also  be
 exposed  (U.S.  EPA,  1980).  Exposure  can occur by  Inhalation,  Ingestlon and
 skin contact  (OSHA/NIOSH, 1980).  Dermal  exposure  to  the general population
 could  result   from  consumer  use  of  dyes  packaged for  home use,  products
 derived  from  3,3'-d1methylbenz1d1ne,  as well  as products  treated with these
 compounds (U.S. EPA, 1980).
     Pertinent  data  regarding  effects  of  3,3'-d1methylbenz1d1ne  on  aquatic
 biota  could not  be  located  In  the  available  literature as  dted  1n  the
 Appendix.
     3,3'-01methylbenz1d1ne  1s' absorbed  after  oral  or  dermal  exposure.  Rats
 treated  orally with  l4C-3,3'-d1methylbenz1d1ne excreted  -40%  of  the  dose
 of  radioactivity  1n the  urine  and -59X 1n the feces  1n  8  days  (Bowman  et
 al.,  1982).   Bowman  et  al.  (1982)  suggested  that  biliary excretion  was
 substantial, since  ~89X  of the  fecal  radioactivity was  present  as  possible
 biliary metabolites.   Thus, gastrointestinal  absorption may  be  as  great  as
 93%.  The  appearance of  3,3'-d1methylbenz1d1ne  1n the  urine  of  occupation-
 ally exposed  humans  Indicates  that dermal  absorption occurs  (Melgs  et  al.,
. 1954).    Following  absorption,   3,3'-d1methylbenz1d1ne  1s widely  distributed
 1n  rats  (Bowman  et  al.,  1982).   Metabolites  Identified  1n  the  urine  of
 exposed rats were  1,l-d1acetyl-3,3'-d1methylbenz1d1ne,  alkaline  hydrolyzable
 conjugates  and monoacetyl-3,3'-d1methylbenz1d1ne as  well as parent compound.

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Metabolites  Identified  1n the  urine  of exposed  workers  were mono- and  d1-
acetyl-3,3'-d1methylbenz1d1ne,  5-hydroxy-3,3'-d1methylbenz1d1ne  and  possibly
3,3'-benz1d1ned1carboxyl1c add.
    Grlswold et al.  (19"68) observed an  Increased  Incidence  of  mammary  tumors
In  rats  treated  by gavage  with  a  total   of  500  mg/rat over  30 days  and
observed for  9 months  compared with  controls.   No tumors  were observed  1n
hamsters treated with  3,3'-d1methylbenz1d1ne  In  the diet  at 0.1 or  0.3%  for
the  Hfespan  (Safflotl  et  al.,   1967;  Sellakumar  et  al.,  1969).    Ferber
(1977) reported a  study 1n which one case  of  bladder cancer was observed  1n
1/4 dogs  8 years  after being  fed  3,3'-d1methylbenz1d1ne at 200  mg/day  for
8-9 months.  3,3'-01methylbenz1d1ne 1s  being tested  by  the  National  Toxicol-
ogy  Program (NTP,  1986).   Preliminary pathological results  Indicate  that
3,3'-d1methylbenz1d1ne administered 1n  drinking water Induces  a  carcinogenic
effect In F344 rats (Mennear, 1987).
    There  are  numerous positive  cardnogenlcHy  studies  for  3,3'-d1methyl-
benzldlne as well as some  that  are negative.   Overall the animal evidence  1s
considered sufficient using EPA's we1ght-of-evidence criteria (Group  B2).
    Several  positive  cardnogenlcHy  studies  by  Injection  and  subcutaneous
administration  were available as  well.   In  rats  given  subcutaneous doses  of
3,3'-d1methylbenz1d1ne, tumors  were observed  In  the Zymbal  gland, preputlal
gland, forestomach, skin,'lung  (PUss and Zabezhlnsky,  1970),  heart  (rhabdo-
myosarcoma) (Pllss and VoVfson, 1973)  and  external  auditory canal (Spitz  et
al.,  1950).   In-  rats  subcutaneously Implanted  with  pellets  containing
3,3'-d1methylbenz1d1ne, Zymbal gland,  mammary  gland, skin,  liver and hemato-
poletlc system tumors were observed (PUss and  Zabezhlnsky,  1970).  Increased
Incidences  of mammary and  lung  tumors were  observed  1n  the  offspring of mice
Injected subcutaneously during gestation (Golub et  al.,  1974).

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    The  possible carcinogenic  effects  of  3,3'-d1methylbenz1d1ne  In  humans
are not  assessed  adequately  to  determine the  direct effect of 3,3'-d1methyl-
benzldlne  alone.   Urinary system  cancer In  workers  exposed to  mixtures  of
benzldlne,   3,3'-d1methylbenz1d1ne   and  3,3'-d1methoxybenz1d1ne   has   been
reported  (MacAlplne,  1947;  Kuratsune and Takemura,  1969);  however, adequate
1nterpret1on of  these  results are  confounded  by the presence of benzldlne, a
known human bladder carcinogen.
    The  mutagenlclty  of  3,3'-d1methylbenz1d1ne has  been  tested  In  various
prokaryotlc  and  eukaryotlc  systems.   3,3'-01methylbenz1d1ne gave predomi-
nantly positive  results  1n frameshlft  sensitive tester  strains  of Salmonella
typhlmurlum  after  liver  S-9   metabolic activation  (Reid   et  al.,  1984a;
Waalkens  et al.,  1981;   Anderson  and  Styles,  1978; Kenelly et  al.,  1984;
Lazear  and  Louie,   1977; Prlval   et   al.,   1984;  Ferettl   et  al.,  1977).
Positive  results  were obtained  1n  DNA  repair  tests  In  the  Escher1ch1a  coll
            *
growth'  differential   test   (N1sh1oka  and   Ogasawara,   1978),   hepatocytes
Isolated  from  rats  and hamsters,  and 1n HeLa cells  with rat liver metabolic
activation  (Martin  et al.,  1978).  Positive  results were  obtained 1n  the
\
sex-Hnked  recessive  lethal  test using  Drosophlla  melanoqaster  after feeding
adult  males   3,3'-d1methylbenz1d1ne   (Valencia et   al.,   1985).    Negative
results,  however, were found In DrosophUa  for the  Induction of  reciprocal
translocatlons-.   Positive results   were  obtained  In  a  mlcronucleus test  1n
rats  (C1hak,  1979),  In   a  testlcular  DNA  synthesis test  1n mice (Seller,
1977) and  1n a ce.ll transformation  test  1n  rat  embryo cells  (Freeman et  al.,
1973).
    The  teratogenldty  of  3,3'-d1methylbenz1d1ne  has   not   been  adequately
assessed  by  a  relevant route of administration.   WHson (1955)  observed  no
malformations  1n progeny of   pregnant  rats   subcutaneously  Injected  with

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3,3'-d1methylbenz1d1ne, but  did  observe a -7%  Increase  of  resorptlons.   Ema
et al.  (1984)  did  not observe fetotoxlc effects  In  progeny of rat dams  sub-
cutaneously  Injected  with 3,3'-d1methylbenz1d1ne.   Pertinent  data regarding
the reproductive  effects  of  3,3'-d1methylbenz1d1ne  could not be  located  1n
the available literature as cited 1n the Appendix.
    The  chronic  and  subchronlc  toxldty of  3,3'-d1methylbenz1d1ne has  not
been studied.
    The  lack  of  subchronlc and chronic  toxldty  data  on 3,3'-d1methylbenz1-
dlne precludes  the derivation of  an RfD or  RQ.  3,3'-01methylbenz1d1ne  1s
considered to  be an  animal carcinogen based on  the  results of subcutaneous.
Injection and  oral  studies.   The U.S.  EPA  (1986a)  listed an  F  factor of  34
(mg/kg/day)""1.   This   F   factor   would  place  3,3'-d1methylbenz1d1ne   In
Potency  Group  2.    U.S.   EPA (1986a)   assigned  an  EPA  we1ght-of-evidence
classification of  C;  however, this  assessment  amends that  classlflctlon  to
Group  82 and  a  medium hazard ranking  under  CERCLA.  A preliminary q *  of
9.2 mg/kg/day'1  was  derived  from  the  Grlswold  et  al.  (1968)  study.   When
the  current  NTP  study  becomes  available,   the  carcinogenic   potency  of
3,3'-d1methylbenz1d1ne will be reevaluated.
                                      1x

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                              TABLE  OF  CONTENTS
                                                                       Page
1.  INTRODUCTION.	    1

    1.1.   STRUCTURE AND CAS NUMBER	    1
    1.2.   PHYSICAL AND CHEMICAL PROPERTIES 	    1
    1.3.   PRODUCTION DATA	    2
    1.4.   USE DATA	    2
    1.5.   SUMMARY	    4

2.  ENVIRONMENTAL FATE AND TRANSPORT PROCESSES	    5

    2.1.   WATER	    5

           2.1.1.   Hydrolysis	    5
           2.1.2.   Oxidation	    5
           2.1.3.   Photolysis	    5
           2.1.4.   Other Chemical Reactions	    6
           2.1.5.   B1odegradat1on	    6
           2.1.6.   Adsorption	    6
           2.1.7.   Volatilization	    6
           2.1.8.   Bloaccumulatlon 	    7

    2.2.   AIR	    7

           2.2.1.   Reaction with Hydroxyl Radicals 	    7
           2.2.2.   Reaction with Ozone 	    7
           2.2.3.   Photolysis	"   7

    2.3.   SOIL	    7

           2.3.1.   Chemical and H1crob1al Degradation	    7
           2.3.2.   Adsorption	    8
           2.3.3.   Volatilization	    8

    2.4.   SUMMARY	    9

3.  EXPOSURE	   10

4.  PHARMACOKINETCS .	   11

    4.1.   ABSORPTION	   11
    4.2.   DISTRIBUTION	   11
    4.3.   METABOLISM	   12
    4.4.   EXCRETION	   12
    4.5.   SUMMARY	   13

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                           TABLE  OF  CONTENTS (cont.)

                                                                        Page
 5.  EFFECTS .  .  ;	   14

     5.1.   CARCINOGENICITY	   14

            5.1.1.    Animal Studies	   14
            5.1.2.    Human Studies 	   17

     5.2.   MUTAGENICITY	   18
     5.3.   TERATOGENICITY	   22
     5.4.   OTHER REPRODUCTIVE EFFECTS 	   22
     5.5.   CHRONIC AND SUBCHRONIC TOXICITY	   22
     5.6.   OTHER RELEVANT INFORMATION 	   22
     5.7.   SUMMARY	   23

 6.  AQUATIC TOXICITY	   26

 7.  EXISTING GUIDELINES AND STANDARDS 	   27

     7.1.   HUMAN	   27
     7.2.   AQUATIC	   27

 8.  RISK ASSESSMENT	   28

 9.  REPORTABLE QUANTITIES 	   34

     9.1.   REPORTABLE QUANTITY (RQ) RANKING BASED ON CHRONIC
            TOXICITY	   34
     9.2.   HEIGHT OF EVIDENCE AND POTENCY FACTOR (F=1/ED10)
            FOR CARCINOGENICITY	   34

10.  REFERENCES	   37

APPENDIX: LITERATURE SEARCHED	   48
                                      x1

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                               LIST OF TABLES

No.                               Title                                Page

1-1     Manufacturers or Importers of 3,3'-D1methylbenz1d1ne
        In 1977	    3

5-1     Mammary Tumor Incidence 1n 45-Day-Old Female Sprague-
        Dawley Rats Given 50 mg 3,3'-01methylbenz1d1ne of
        Unspecified Purity 1n Sesame 011 at 3-Day Intervals for
        30 Days, Followed by a 9-Month Observation Period 	   15

5-2     MutagenlcHy Testing of 3,3'-D1methylbenz1d1ne	   19

8-1     Derivation of Potency Factor (F factor) for
        3,3'-D1methylbenz1d1ne	   32

9-1     3,3'-D1methylbenz1d1ne: Minimum Effective Dose (MED) and
        Reportable Quantity (RQ)	   35

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                             LIST OF ABBREVIATIONS

ADI                     Acceptable dally Intake
BCF                     B1oconcentrat1on factor
CAS                     Chemical Abstract Service
DNA                     Deoxyr1bonucle1c acid
FMN                     Flavin mononucleotlde
Koc                     Soil sorptlon coefficient standardized
                        with respect to organic carbon
Kow                     Octanol/water partition coefficient
HTO                     Maximum tolerated dose
ppb                     Parts per billion
RfD                     Reference dose
RQ                      Reportable quantity
TLV                     Threshold limit value
TRNA                    Transfer rlbonuclelc add
TWA                     Time .-weigh ted average
UDS                     Unscheduled ONA synthesis
UV                      Ultraviolet

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                               1.  INTRODUCTION
1.1.   STRUCTURE AND CAS NUMBER
    3,3'-D1methylbenz1d1ne  1s  also known as  o-to!1d1ne,  3,3'-d1methy1-l ,V-
b1phenyl-4,4'-d1am1ne,  d1am1nod1tolyl  and  C.I.  Azoic 01azo  Component  113
(C.I.  37230).   The  structure,  molecular weight,  empirical  formula  and  CAS
Registry number for 3,3'-d1methylbenz1d1ne are as follows:
                          H,C                   CH,
Molecular weight:  212.28
Empirical formula:  CT4HigN2
CAS Registry number:  119-93-7
1.2.   PHYSICAL AND CHEMICAL PROPERTIES
    3,3'-D1methylbenz1d1ne  1s a  white  to  reddish  crystalline  compound  at
ambient  temperature  (Wlndholz,  1983).   It  1s  a weak  base (IARC, 1972)  and
Us reactions  are s1m1!1ar to those  of  benzldlne, which  undergoes  chemical
reactions characteristic  of  primary  arylamlnes  as  well  as those reactions
related  to  Us  dlfunctlonal  character such  as  oxidation to qulnonold  struc-
tures  and  copolymerlzatlon  (Ferber,  1978).   3,3'-D1methylbenz1d1ne  forms
Intense  blue  compounds  with  chlorine  and bromine vapors  (Lurle,  1964).
3,3'-D1methylbenz1d1ne  Is  soluble   In  alcohol,  ether   and  dilute   adds
(Wlndholz, 1983).  Selected physical  properties are as  follows:
Melting point:
Boiling point:

Vapor pressure at 20*C:
129-13TC
416-419°C
(estimated)
2.7xlO"7 mm Hg
(estimated)
Wlndholz, 1983
Neely and Blau, 1985

Neely and Blau, 1985
0857p
  -1-
                04/10/87

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Water solubility at 25°C:         2400 rng/l          Lyman et al., 1982
                                  (estimated)        (equation 2-2)
Log Kow:                          2.34               Hansch and Leo, 1985

1.3.   PRODUCTION DATA
    3,3'-D1methylbenz1d1ne  1s  made by  the  reduction of  o-n1trotoluene with
zinc  dust  and  caustic   soda   to   hydrazotoluene,   which  Is  subsequently
rearranged  by  boiling  with  sulfurlc  or  hydrochloric  acid  (Lurle,  1964;
Powell et al.,  1979).   Organic diluents such as  solvent  naphtha and alcohol
are  used to  moderate  this vigorous  reaction  (Lurle,  1964).   No  current
commercial manufacturers of 3,3'-d1methylbenz1d1ne  1n the United States were
reported  (SRI,  1986;  USITC, 1985).  Table  1-1  lists the  U.S.  manufacturers
or Importers of this compound  1n 1977 and their  production volumes.
    In  1978,   Upjohn  discontinued   manufacturing  this   compound  and  began
Importing  H  (Powell et  al.,  1979).    In  1983,  75,307  pounds   of  3,3'-d1-
methylbenzldlne  was  Imported   Into  the  United   States   through  principal
customs districts (USITC, 1984).
1.4.   USE DATA
    It 1s estimated that >75% of  the 3,3'-d1methylbenz1d1ne  consumed Is used
as an  Intermediate 1n  the production  of dyes  and  pigments (Powell  et al.,
1979).   Twenty-two  azo  dyes  are produced  domestically  from  3,3'-d1methyl-
benzldlne (U.S.  EPA,  1980), the  most  Important  of  which are Direct  Red  2,
Direct  Red  39  and  Direct Blue  25  (Ferber,   1978).   The  use   pattern  for
benz1d1ne-based dyes  1s  as follows:  paper coloring, 40%;  textile coloring,
25%;  leather  coloring,  15%;  diverse applications  1n  the petroleum,  rubber
plastics, wood,  soap,  fur and  hair  dye  Industries,  20%  (NIOSH,  1980).
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                                  TABLE  1-1
         Hanufacturers  or  Importers  of  3,3'-D1methylbenz1d1ne  1n  1977*
Company/Location
The Upjohn Co.
North Haven, CT
Aceto Chem Co., Inc.
Flushing, N.Y.
American Hoechst Corp.
Brldgewater, NJ
Nagase America Corp.
New York, NY
GAP Corp.
New York, NY
Manufacturer
or Importer
manufacturer
Importer
Importer
Importer
Importer
Production/Import Volume
(million pounds)
confidential
0.010-0.100
confidential
0.010-0.100
0.001-0.010
*Source: U.S. EPA, 1977
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Approximately 20%  of  3,3'-d1methylbenz1d1ne  consumed  domestically 1s used 1n
the  production  of  polyurethane-based high strength elastomers,  coatings and
rigid plastics.  3;3'-D1methylbenz1d1ne  Is also used  for  chlorine detection
and  other  laboratory  procedures;  however,   this  accounts  for   <5% of  the
3,3'-d1methylbenz1d1ne used domestically (Powell et al., 1979).
1.5.   SUMMARY
    3,3'-D1methylbenz1d1ne  1s  a  white  to reddish crystalline   compound  at
ambient  temperature.   It  Is  sparingly  soluble 1n water  and 1s  soluble  In
ether, alcohol  and dilute  acids  (VMndholz,  1983).   It 1s  a weak  base and
undergoes  reactions  similar  to  those  of  benzldlne  (IARC,  1972;  Ferber,
1978).   3,3'-01methylbenz1d1ne  Is  made by  the  reaction  of  o-n1trotoluene
with  zinc dust  and caustic  soda  to  form hydrazotoluene,. which  1s  subse-
quently  rearranged by  boiling  with  sulfurlc  or  hydrochloric  add  {Lurle,
1964;  Powell  et   al.,   1979).   No   current   commercial   manufacturers  of
3,3'-d1methylbenz1d1ne 1n the United States were  reported  (SRI,  1986;  USITC,
1985).  In 1983, 75,307  pounds of this  compound was  Imported Into the United
States through  principal customs districts  (USITC,  1984).   It  1s estimated
that >75X of  the 3,3'-d1methylbenz1d1ne  consumed 1s used  as  an  Intermediate
1n the production  of azo dyes and pigments used for  coloring paper, textiles
and  leathers  and  for   diverse  applications   In  the  petroleum,  rubber,
plastics, wood,  soap,  fur  and  hair dye  Industries   (Powell  et  al.,  1979;
NIOSH,  1980).   Approximately  20%   of   the  3,3'-d1methylbenz1d1ne  consumed
domestically  Is  used  In  the production  of polyurethane-based high strength
elastomers,   coatings   and  rigid  plastics and <5%   1s  used  for  chlorine
detection and other laboratory  procedures (Powell  et  al., 1979).
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                2.  ENVIRONMENTAL FATE AND TRANSPORT PROCESSES

    3,3'-01methylbenz1d1ne  1s   a  weak  base  that  may  be  protonated  under
acidic conditions to  form salts that are more  water  soluble  than the parent
compound.   Protonatlon  can alter  the behavior  of a  compound 1n water  and
soil,  for  example,  by  decreasing volatilization  as   well  as  Increasing  or
decreasing adsorption to soil,  sediments  and suspended solids  In water.
2.1.   WATER
2.1.1.   Hydrolysis.   Based  on  the  structure  of  3,3'-d1methylbenz1d1ne,
this compound 1s likely to be  resistant to hydrolysis  (Lyman et a!.,  1982).
2.1.2.   Oxidation.    Pertinent   data  regarding   the  oxidation  of   this
compound could  not  be  located  In the available  literature as cited  1n  the
Appendix;   however,  unsubstHuted   benzldlne  Is  very  rapidly oxidized  by
Fe(*3) and  other  naturally occurring  cations  found 1n  natural waters  (U.S.
EPA,  1979).   Because  of  the  two methyl  substltuents  on the  aromatic  ring,
3,3'-d1methylbenz1d1ne may  have a higher tendency  to  undergo  this  oxidation
by metal cations.   Based  on the fate of  benzldlne 1n  water  (U.S.  EPA, 1979),
oxidation by  other  oxldants  Including molecular  0_   and  H02  radicals  will
also take place, although oxidation  by metal  cations  1n  natural water may be
more rapid.  On  the basis of  the estimated oxidation  half-life of  benzldlne
In natural  water  (U.S.  EPA, 1979),  the  half-life of  3,3'-d1methylbenz1d1nes
1s estimated to be <4 hours.
2.1.3.   Photolysis.   D1methylbenz1d1ne   1n  methanol   strongly  absorbs  UV
light  1n  the  environmentally  significant  wavelength   range  of   >290  nm
(Sadtler, n.d.).  These data Indicate that direct photolytlc  reactions  may
be significant  1n  removing 3,3'-d1methylbenz1d1ne  from  water.  Experimental
             •>
data on  the photolysis  of  this  compound  could not be located  In  the avail-
able literature as cited In the Appendix.

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2.1.4.   Other Chemical  Reactions.   Schmltz and  Rooze  (1981)  reported  that
3,3'-d1methy1benz1d1ne reacts  rapidly with chlorine and  with chlorine diox-
ide  1n  aqueous  solution,  suggesting  that  these reactions  could contribute
significantly  to  the  removal of  3,3'-d1methy1benz1d1ne  from water,  particu-
larly during the disinfection of drinking water.
2.1.5.   Blodegradatlon.    Pertinent  data   regarding  the  blodegradatlon  of
3,3'-d1methylbenz1d1ne were  limited.   An  aerobic  blodegradatlon  screening
study  using   20  mg/i  3,3'-d1methylbenz1d1ne   Inoculated   with  activated
sludge at  25°C  resulted  1n  99-100%  depletion  of the  parent compound  1n  6
hours  (Balrd   et  al., 1977).   The metabolic  Intermediates,  however,  were
speculated  to  be  toxic   to  microorganisms  and  the  oxygen consumption  1n
experiments with 3,3'-d1methylbenz1d1ne was less than  the endogenous  process.
2.1.6.   Adsorption.   Based  on  observed covalent binding  of primary  amines
to  humates  (Parrls,  1980)  and   the   estimated  K     of  60-271   (Section
2.3.2.),  physical  adsorption and  covalent bonding to  suspended solids  and
sediments  1n water  may be significant.   In fact, based on  the studies  with
benzldlne  and  3,3'-d1chlorobenz1d1ne  (U.S.  EPA,  1979)   1t  1s  likely  that
adsorption  by  suspended  mlcrocrystalUne  clays  may  be  the most  Important
process and the half-life of  that  process may be <1  hour.
2.1.7.   Volatilization.    3,3'-01methylbenz1d1ne  should   not  volatilize
significantly   from water  because  of  possible  protonatlon  In water  at pH<7.
The adsorption  to mlcrocrystalllne clays  and  covalent  binding  with humates
1n water will  also  reduce volatility.  The volatility may be higher at  pH>7
than at pH<7.
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2.1.8.   B1oaccurou1at1on.   The  BCF   for   3,3'-d1methylbenz1d1ne  has  been
estimated  using  the  following recommended  linear regression equations  (Lyman
et a!., 1982):
                         log BCF  =  0.76 log KQW - 0.23                  (2-1)
                      log BCF  = 2.791  - 0.564 log S(rag/1J                (2-2)
Based  on  the estimated  log   K    of  2.34 and  solubility of  2400  mg/i  at
25°C,  the  BCF for  3,3'-d1methylbenz1d1ne has  been  calculated  to be 35 and 8
from  Equations  2-1 and  2-2,  respectively.   These  BCF values  Indicate that
3,3'-d1methylbenz1d1ne  should  not  bloaccumulate  significantly  In  aquatic
organisms.
2.2.   AIR
2.2.1.   Reaction  with   Hydroxyl   Radicals.    3,3'-01methylbenz1d1ne  1n  the
vapor  phase  will  react  1n  the   atmosphere  with  photochemlcally generated
hydroxyl  radicals.   The hydroxyl  reaction rate constant  has  been estimated
to  be 6.02X10"11  cmVmolecule-sec at  25°C.   Assuming an ambient hydroxyl
radical  concentration  of  8.0x10=  molecules/cm3,   the  reaction  half-life
has been estimated to be 4.0 hours  (U.S. EPA, 1986b).
2.2.2.   Reaction with  Ozone.   3,3'-01methylbenz1d1ne 1s  not susceptible  to
oxidation by ozone (U.S. EPA,  1986b).
2.2.3.   Photolysis.    Since   3,3'-d1methylbenz1d1ne   In   methanol  strongly
absorbs UV  light of  wavelengths >290  nm  (Sadtler,   n.d.),  direct photolysis
may be significant In the troposphere.
2.3.   SOIL
2.3.1.   Chemical and M1crob1al  Degradation.   Pertinent  data  regarding  the
chemical  or  mlcroblal  degradation of  3,3'-d1methylbenz1d1ne  In  soil  could
not be  located  1n  the  available literature.   Based  on the molecular struc-
ture of  3,3'-d1methylbenz1d1ne,  this compound  Is likely  to be  resistant  to
0857p                               -7-                              06/10/87

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hydrolysis  (Lyman et  al.,  1982).   Benzldlne,  a  cogener  of 3,3'-d1methyl-
benzldlne  Is  reported  to  undergo  rapid  oxidation   In  clay  soils with  a
half-life  of  <1  day (U.S.  EPA,  1980;  Lapp et al., 1981).   Therefore,  H Is
expected  that 3,3'-d1methylbenz1d1ne will  also undergo  this soil-catalyzed
oxidation and the half-life of this reaction may be <1 day.
2.3.2.   Adsorption.   ParMs (1980) experimentally  determined  that primary
amines  covalently bind  to  humates (soil  organic  matter)  Initially  by  a
rapid,  reversible   reaction  followed   by   a  slower  Irreversible  binding
process.   The K   for 3,3'-d1methylbenz1d1ne has  been calculated  using  the
following linear regression equations (Lyman et al.,  1982):
                      log KQC = -0.55 log S(mg/l) + 3.64                (2-3)
                  log KQC = -0.54 log S(mol fraction)  + 0.44            (2-4>-
Based  on  a water  solubility  of  2400  mg/l  at  25°C,  KQ(.  values  of 60  and
271  were  calculated from  Equations 2-3  and  2-4,  respectively.   These  K
values  suggest  that  3,3'-d1methylbenz1d1ne may be moderately mobile 1n soil
(Swann et al., 1983);  however,  since benzldlne and  substituted benzldlne  are
known  to  adsorb strongly  and rapidly  to  mlcrocrystalUne clays  (U.S.  EPA,
1979),  3,3'-d1methylbenz1d1ne may  be  significantly  Immobilized  1n certain
soil  types  by  physical  adsorption and  covalent binding.   In  addle  soils
some mobilization of the compound Is expected because  of protonatlon.
2.3.3.   Volatilization.    Pertinent  experimental data  regarding volatiliza-
tion of 3,3'-d1methylbenz1d1ne  1n soil could  not be located In the available
literature as  cited  1n  the Appendix.   Based  on the  water  solubility  (2400
mg/l  at 25°C),  possible  protonatlon  1n  acidic  soils  and  adsorption  and
covalent binding to  soils  (see Section  2.3.2.), volatilization  from wet  and
dry soil surfaces 1s  not  expected to be  significant.
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2.4.   SUMMARY
    3,3'-D1methy1benz1d1ne Is a weak base and  as  such,  may be protonated and
form  salts  that are  more soluble  than  the parent compound.   Variations  In
the  behavior  of 3,3'-d1methylbenz1d1ne  In  the  environment  may  result  from
protonatlon.  If released  to water,  3,3'-d1methylbenz1d1ne 1s  expected  to  be
oxidized by  Fe{+3)  and other cations  fairly  rapidly (U.S.  EPA,  1979).   The
half-life of  this  oxidation  may be  <4  hours.   It Is likely  to  be  resistant
to  hydrolysis   (Schmltz  and  Rooze,  1981;   Lyman  et  al..  1982).   Potential
exists for  significant photolysis  of 3,3'-d1methylbenz1d1ne.   Adsorption  to
mlcrqcrystalUne clay  and  covalent  binding  to  suspended  solids and  sediments
may be  significant  (U.S.   EPA, 1979;  ParMs,  1980).   In fact,  adsorption  by
mlcrocrystalUne clays may be the most  Important  process  In  water.   Bloaccu-.
mulatlon In  aquatic organisms and  volatilization from  water  should not  be
significant  removal  processes.    If released  to air,  vapor  phase  3,3'-d1-
methylbenzldlne  1s  predicted to  react  with   hydroxyl  radicals  and  has  an
estimated half-life of 4.0 hours at  25°C (U.S.  EPA,  1986b).   Direct photoly-
sis In the troposphere 1s  also Hkely  to be a  significant  removal mechanism.
Reaction with  ozone  Is  unlikely  (U.S.  EPA,  1986b).   If  released  to  soil,
3,3'-d1methylbenz1d1ne Is  likely  to be  resistant  to  hydrolysis  (Lyman  et
al.,  1982).   3,3'-D1methylbenz1d1ne may be Immobilized  1n soil  by  physical
adsorption   and  covalent  binding.    Some  mobilization  may  occur In  acidic
soils because of protonatlon.  Volatilization  from wet and dry soil  surfaces
should not be  significant.  Soil-catalyzed  oxidation of  3,3'-d1methylbenz1-
dlne may be the most  significant reaction of this chemical and the  half-life
of this reaction may be <1 day (U.S. EPA, 1980; Lapp  et  al.,  1981).
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                                 3.  EXPOSURE

    Monitoring data  regarding  3,3'-d1methylbenz1d1ne  could not be located In
the  available  literature  as  cited  1n  the  Appendix.   This compound  1s  not
known  to occur  naturally  In  the  environment  (U.S.  EPA,  1980).   Potential
sources  of  major release are  1n  airborne partlculate matter  and wastewater
from manufacturing and  processing  plants for dyes and  pigments  derived from
3,3'-d1methylbenz1d1ne (U.S. EPA,  1980;  Lapp et al.,  1981).
    Minor  sources  of  release  may  originate  from  clothing,  colored  paper,
textiles, leather and  other  dyed  materials  that are  commonly  disposed of 1n
solid waste disposal  sites  (U.S.  EPA, 1980).
    The workers  who  manufacture and  handle 3,3'-d1methylbenz1d1ne-based dyes
and  pigments  are likely  to be the  most  exposed  segment of  the population
(U.S.  EPA,  1980).   Urine  samples  from  some  workers  exposed  to azo  dyes
during manufacture (two  sites) and use (four sites)  contained ppb levels of
3,3'-d1methylbenz1d1ne  (Lowry  et  al.,   1980).   Workers  1n biochemical  and
clinical  laboratories  where  3,3'-d1methylbenz1d1ne   1s   used may  also  be
exposed  (U.S.  EPA,  1980).   Exposure can  occur  by Inhalation,  Ingestlon  and
skin contact  (OSHA/NIOSH,  1980).   Dermal exposure to  the general population
could  result   from  consumer use  of  dyes  packaged  for  home  use,  products
derived from 3,3'-d1methylbenz1d1ne, as  well as products  treated with these
compounds (U.S. EPA,  1980).
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                             4.  PHARMACOKINETICS
4.1.   ABSORPTION
    Bowman et  a1..(1982)  .treated male rats with  single oral  doses that con-
tained  17 yg  of  l*C-3,3'-d1methylbenz1d1ne  (uniformly ring-labeled)  oral
765  yg  of  unlabeled  3,3-d1methylbenz1d1ne-2HCl.   The  vehicle  was  dilute
aqueous  HC1.  After  192  hours,  -40  and  59%  of  the  radioactive dose  was
excreted  1n  the  urine and  feces,  respectively.   As 89%  of the  fecal  radio-
activity  represented  possible biliary  metabolites,  biliary  excretion  may
have accounted  for  the high degree  of fecal excretion.  Therefore,  absorp-
tion by  the  gastrointestinal  tract  may have been  at  least 93%.   Bowman  et
al.  (1982)  did  not  Investigate biliary  excretion  1n  bile duct  cannulated
rats,  however.   Melgs  et al.  (1954)  detected 3,3'-d1methylbenz1d1ne  In  the
urine  of  occupatlonally exposed workers, Indicating that dermal  exposure  of
humans results 1n absorption by this route.
4.2.   DISTRIBUTION
    Bowman et  al.  (1982)  gave  rats  single  oral  doses  of l*C-3,3'-d1methyl-
benzldlne  (see  Section 4.1.)  and  assayed  the tissues  for distribution  72
hours  later.   Radioactivity was widely distributed  to  tissues.   The  highest
levels of 14C were  observed  In the  liver  (0.907  yg  equ1v/g),  lung  (0.459
yg  equ1v/g)  and kidney  (0.130 yg  equ1v/g).   Small  amounts  of  radioactiv-
ity  (0.004-0.048 yg  equlv/g)   were  also  found  In brain,  muscle,  testes,
heart, spleen,  blood  and  urinary  bladder.   Levels In  adipose  tissue  were
below detection levels  (<0.014  yg equ1v/g).
    PUss and  Zabezhlnsky  (1970)  subcutaneously  Injected rats  with 3,3'-d1-
methylbenz1d1ne  1n  sunflower oil  at a  dose  of 20  mg/rat once weekly  for  8
months.  At  3  days  after  the  last  dose, the  rats  were  killed  and the  levels
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of amines  were  measured for several organs.   The  highest amlne levels (free
and  bound  added together)  as  mg/g tissue 1n  descending  order were observed
1n the Zymbal gland', kidney, omentum, spleen and liver.
4.3.   METABOLISM
     Dleteren  (1966)  Identified  the urinary metabolites  of  workers  occupa-
tlonally exposed  to 3,3'-d1methylbenz1d1ne.   The  parent compound  was found
as well  as the metabolites d1acetyl-3,3'-d1methylbenz1d1ne,  5-hydroxy-3,3'-
d1methylbenz1d1ne  or  Us  ester  and possibly  monoacetyl-3,3'-d1methylbenz1-
dlne.  The authors emphasized  that other metabolites  were  present as  well
(e.g., 3,3'-benz1d1ned1carboxyl1c  add,  which  can  be  obtained  by  oxidation
of the methyl groups).
     Bowman  et  al.  (1982)  gave  Fischer  344  rats  single oral  doses  (see
Section  4.1.)  of  l*C-3,3'-d1methylbenz1d1ne  and   Identified the  following
urinary  metabolites:    d1acetyl-3,3'-d1methylbenz1d1ne  (2.IX  of the  dose);
alkaline  hydrolyzable  conjugates   (0.4%);  monoacetyl-3,3'-d1methylbenz1d1ne
(0.2%).  Other  unidentified  metabolites  were present  as  well.   Unchanged
3,3'-d1methylbenz1d1ne  constituted  0.4% of  the  dose.   The Interval of  peak
excretion of metabolites was between 8  and 16 hours.
4.4.    EXCRETION
     Bowman   et  al.  (1982)  gave  Fischer  344 rats  single  oral  doses  of
l4C-3,3'-d1methylbenz1d1ne  (see  Section  4.1.) and  found  that  -40 and  59%
of the  dose of radioactivity  was  excreted  In the  urine and  feces,  respec-
tively, within 192 hours.   About 1-6% of the dose  was  excreted as the  parent
compound.  Urinary and fecal excretion  peaked at 16 hours.
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4.5.   SUMMARY
    3,3'-01methylbenz1d1ne  Is  absorbed after oral  or  dermal exposure.  Rats
treated  orally  with  l*C-3,3'-d1methylbenz1d1ne  excreted -40%  of  the  dose
of  radioactivity In  the  urine and  -59%  1n  the  feces  1n 8  days  (Bowman  et
a!.,  1982).   Bowman  et  al.  (1982)  suggested  that  biliary excretion  was
substantial,  since  -89X of  the  fecal  radioactivity was  present  as  possible
biliary  metabolites.   Thus, gastrointestinal absorption  may be as  great  as
93%.   The  appearance of  3,3'-d1methylbenz1d1ne  In the urine of  occupation-
ally  exposed  humans Indicates that  dermal  adsorption  occurs  (Melgs  et  al.,
1954).   Following  absorption, 3,3'-d1methylbenz1d1ne  1s  widely  distributed
1n  rats   (Bowman et  al.,  1982).   Metabolites   Identified   1n  the  urine  of
exposed  rats  were  d1acetyl-3,3'-d1methylbenz1d1ne,  alkaline  hydrolyzable
conjugates  and monoacetyl-3,3'-d1methylbenz1d1ne  as well  as  parent compound.
Metabolites  Identified  1n  the   urine of   exposed workers  were  mono- and
d1acetyl-3,3'-d1methylbenz1d1ne,      5-hydroxy-3,3'-d1methylbenz1d1ne     and
possibly 3,3'-benz1d1ned1carboxyl1c add.
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                                  5.   EFFECTS
5.1.   CARCINOGENICITY
5.1.1.   Animal  Studies.   Grlswold et al.  (1968)  treated a  group of twenty
45-day-old  female  Sprague-Dawley rats by  gavage with 10  doses  of 50 mg/rat
(total  500  mg/rat) 3,3'-d1methy1benz1d1ne  In sesame oil  at  3-day Intervals
for  30  days,  followed by a 9-month  observation  period  (Table 5-1).  Sixteen
rats  survived  the  observation period.  Rats  that  died  or  were killed at the
end  of  the  study were necropsled.   Hlstologlcal  examination  was performed on
grossly  apparent  lesions,  mammary  glands,  Intestinal  tract,  pituitary,
liver, ovaries  and adrenals.   The mammary tumor  Incidence In treated female
rats  was  3/16;  whereas  an Incidence  of  5/132  was  observed  1n  the  control
data  pooled from  several  experiments.   IARC (1972)  considered  this  experi-
ment  to  be  of  doubtful  significance because of  the  small  number  of  rats'
tested.
     Saff1ott1 et- al.  (1967)  gave groups of  30 male  and 30 female 9-week-old
Syrian  golden   hamsters  0.1%  3,3'-d1methylbenz1d1ne  In  the  diet  for  their
Hfespan.   The  authors estimated  60 mg of  the  test substance  was Ingested
per  week  based  on  food  Intake  data.   Controls  were  given food  that  did not
contain  3,3'-d1methylbenz1d1ne.   No  tumors  were  observed  1n   the  treated
hamsters.   In  a  similar  experiment,  Sellakumar  et  al.   (1969)  reported
negative  results  1n  30  male  and  30  female  hamsters maintained on a  diet
containing 0.3% 3,3'-d1methylbenz1d1ne for the llfespan.
     Ferber  (1977)  reported a study  1n  which four young  mongrel  female dogs
were  given  200 mg  3t3'-d1methylbenz1d1ne  1n capsules  dally  for  8-9  months
for  a total dose  of  50  g/dog.   Cystoscoplc examinations before  and  after
treatment were  negative.  One  of the  four  treated  dogs developed  bladder
cancer  (papillary  tumor  and  cystitis) 8  years   later.   The  remaining  dogs
either died of natural causes or were killed, but no  tumors were observed.

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                                   TABLE  5-1

    Mammary Tumor Incidence 1n 45-Day-Old Female Sprague-Oawley Rats Given
    50 mg of 3,3'-01methylbenz1d1ne of Unspecified Purity 1n Sesame 011 at
    3-day Intervals for 30 Days, Followed by a 9-Month Observation Period*
                         Dose
                           Incidence
                      50 mg/rat
                  (500 mg total dose)
                                               5/132 (-
                          3/16 (-19%)
                          (NS)
Strength of Study:


Weakness of Study:
Overall Adequacy:
         QUALITY  OF  EVIDENCE

A relevant  route of administration  was  'used.
was established by pre-testlng.
                The  MTO
Only one  sex  of  one species was  tested.   Only one dose
was tested and the  duration  of  exposure was not for the
Hfespan  of  the  organism.   A  limited  number  of organs
were  examined  hlstologlcally   and  the  data  were  not
statistically analyzed.
Valid  for  we1ght-of-ev1dence,
analysis
limited  for  statistical
*Source: Grlswold et al., 1968
0857p
               -15-
                06/10/87

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    3,3'-D1methylbenz1d1ne   Is   being   tested  for  carclnogenlclty  by  the
National  Toxicology  Program {NTP, 1986).   Preliminary  results Indicate that
3,3'-d1methylbenz1d1ne  Induces  a carcinogenic  effect  1n F344  rats  when the
compound  1s administered 1n drinking water (Mennear, 1987).
    Several  studies  that  used  less relevant  routes of  administration were
located  In  the available literature.  PUss  and  Zabezhlnsky (1970)  subcuta-
neously  Injected  27 male  and  26 female  rats with  20  mg/rat 3,3'-d1methyl-
benzldlne  1n  sunflower  oil  once weekly for  13  months  and observed tumors  1n
60% of  the treated  rats.   The  first  tumor appeared at  8  months,  at  which
time 25  rats/sex  survived.   Zymbal  gland tumors  (14/25 males,  6/25  females)
were  the  primary  tumor  type   observed,  but  tumors also  developed In  the
preputlal  gland  (2/25  males,  1/25  females),  forestomach (2/25  males,  0/25
females),  skin  (2/25  males,  1/25 females) and mammary  gland (5/25 females).
No  treatment-related  tumors were observed  1n a  group  of  50 control  rats
Injected  subcutaneously  with   sunflower   oil   (Pllss,   1963).    Pllss  and
Zabezhlnsky  (1970)  also subcutaneously  Implanted  pellets  containing  20  mg
3,3'-d1methylbenz1d1ne  1n  24 male  and 24  female  rats,  once weekly for  14
months.  The first tumor appeared at 12 months  at which time 16 males and  20
females  were   alive.    The  treated  rats  developed  primarily Zymbal  gland
(6/16  males,  5/20  females)  and  mammary gland  tumors  (7/20 females,  0/16
males).  Tumors of the  skin, liver and  hematopoletlc system were  observed  as
well.   PUss and Vol'fson  (1973)  observed a  rhabdomyosarcoma of  the  heart  In
rats subcutaneously  Injected,  once  weekly with 10  mg  3,3'-d1methylbenz1d1ne
for 33 weeks.   Holland et  al.  (1974)  reported  that  18/21  rats  given  a
cumulative  subcutaneous  dose of  5.4  g/kg over  241 days developed  tumors.
0857p                               -16-                             06/10/87

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SpHz  et  al.  (1950) observed  no  cirrhosis of the liver  or  hepatomas 1n 105
rats  subcutaneously  Injected with  60 mg  3,3'-d1methylbenz1d1ne  once weekly
for  a  total  dose  of   5.5  g.   Cancer  of  the external  auditory  canal  was
observed 1n 4.3X of the treated rats.
    Golub et al.  (1974) subcutaneously  Injected  BALB/c  mice  with  2 mg/lnjec-
tlon of 3,3'-d1methylbenz1d1ne  In  sunflower  oil  4 or  5  times during the last
week of pregnancy.   The control group consisted  of  the progeny of untreated
dams.   No  effects of treatment were reported In the dams.   Survival  of the
progeny of  treated  dams  was  diminished;  however, no  additional  data  were
provided.   The  progeny of  treated dams had  a higher  total  tumor Incidence
(13/24, 50%)  compared  with controls  (6/30,  20X).   Major  types  of  tumors
observed In treated mice were lung and mammary tumors.
5.1.2.   Human.    MacAlplne  (1947)  reported  two  cases  of  urinary  tract
tumors, which eventually resulted  1n death of workers occupatlonally exposed
to  benzldlne and  3,3'-d1methylbenz1d1ne.   Kuratsune  and  Takemura  (1969)
reported 23  cases of  urinary  system cancer  1n  Japanese workers  exposed  to
                     *#
benzldlne,  3,3'-d1methylbenz1d1ne  and 3,3'-d1methoxybenz1d1ne.   Fourteen  of
these workers were exposed  for  <6  years.   The workers exposed 1n these cases
were also exposed to benzldlne, a  known  bladder  carcinogen.   A review of the
carcinogenic effects  observed  1n  workers  of the dyestuff  Industry  can  be
found  1n  several publications  (NIOSH,  1978,  1980;  OSHA/NIOSH,  1980).   The
available  ep1dem1olog1c data clearly  show  that benzldlne  base dyes are human
carcinogens.    The  data  also  show that  benzldlne  1n  combination  with
3,3'-d1methyl-  and d1methoxybenz1d1ne Is  carcinogenic  to humans.   There Is,
however, no data available for dlmethylbenzldlne  alone.
0857p                               -17-                             06/10/87

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5.2.   MUTAGENICITY
    The  ability  of  3,3'-d1methylbenz1d1ne  to cause  point mutations  1n  the
Salmonella  typhlmurlum  hlstldlne reverse mutation  test  Is  well  established
(Table  5-2).   In  general,  3,3'-d1methylbenz1d1ne  was  mutagenlc  In  frame-
sh1ft-sens1t1ve tester  strains  (namely,  TA98 and TA1538)  1n  the  presence of
rat, mouse  or  hamster  Hver  S9  metabolic  activation  (Reid  et  al.,  1984a,b;
Waalkens et al., 1981;  Kennelly  et  al.,  1984;  Lazear  and Louie, 1977;  PMval
et  al.,  1984;  Anderson and  Styles,  1978;  Ferrettl  et  al.,  1977).   Negative
or  weakly  positive  results  were obtained  In base-pair  substitution  tester
strains (I.e.,  TA1535, TA1537, TA100) of Salmonella.
    N1sh1oka and   Ogasawara   (1978)  obtained  positive  results  In  a  growth
differential  test   of  Escher1ch1a   coll   using DNA  repair-deficient  and
proficient strains.   Kornbrust and  Barfknecht  (1984,  1985) observed positive
results  1n  ONA  repair  tests  using  hepatocytes   Isolated   from  both  male
Sprague-Dawley  rats  or  male  Golden  Syrian  hamsters.   3,3'-01methylbenz1d1ne
Induced  unscheduled  DNA synthesis  In Hela  cells   with  rat  Hver  metabolic
activation  (Martin et al., 1978).   In  the  sex-1Inked  recessfve  lethal  test
1n  DrosophUa  melanoqaster.  positive  results  were  obtained when  3,3'-d1-
methylbenz1d1ne  was  administered   by   feeding  adult   males  and   produced
equivocal results  after adult Injection  (Valencia  et al.,  1985).   However,
3,3'-d1methylbenz1d1ne  did not  Induce  reciprocal  translocatlons  In  Droso-
phlla  (Valencia   et   al.,   1985).    A  statistically  significant  treatment-
related Increased  frequency  of mlcronucleated  polychromatic  erythrocytes  was
observed In bone marrow smears from  Wlstar  rats  given 3,3'-d1methylbenz1d1ne
1n  olive  oil  by stomach  tube (C1hak,  1979).   Testlcular DNA  synthesis  was
Inhibited  1n  mice   given  3,3'-d1methylbenz1d1ne  orally  (Seller,   1977).
Freeman et  al.  (1973) obtained  positive results In ^n  vitro transformation
tests using Fischer rat embryo cell  line F1706 P88.

0857p                               -18-                             06/10/87

-------
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5.3.   TERATOGENICITY
    Pertinent  data  regarding  the  teratogenlclty  of  3,3'-d1methylbenz1d1ne
administered  by the  oral  or  Inhalation  route could  not  be  located  In the
available  literature  as cited  1n the  Appendix.   Wilson  (1955)  observed no
malformations  1n  progeny  of  rats  subcutaneously  Injected  with  30 mg of
3,3'-d1methylbenz1d1ne  on  days 7,  8 and  9  of gestation.   The  Incidence of
resorptlons  was  -7%.   No  control   data  or  maternal  toxldty  data  were
reported.   Ema  et  a "I.  (1984)  observed  no fetotoxldty  1n progeny of Wlstar
rat  dams  subcutaneously  Injected with  3,3'-d1methylbenz1d1ne  on day  7 of
pregnancy.
5.4.   OTHER REPRODUCTIVE EFFECTS
    Pertinent  data regarding  other  reproductive  effects  of  3,3'-dlmethyl-
benzldlne  could  not be located  1n  the  available  literature as  cited In the
Appendix.
5.5.   CHRONIC TOXICITY
    Pertinent  data regarding  the oral  or  Inhalation  chronic  or  subchronlc
toxlclty  of 3,3'-d1methylbenz1d1ne  could not  be  located In  the available
literature as cited In the Appendix.
5.6.   OTHER RELEVANT INFORMATION
    Sololmskaya  (1970)  subcutaneously Injected rats with  100  mg/kg 3,3'-d1-
methylbenzldlne  and  observed  Increased  monoamlne  oxldase and  hlstamlnase
activity.   In  rats  subcutaneously Injected with 100 mg/kg once  weekly for  2
months.  Increased-  activity of the  enzymes catalyzing  oxldatlve deamlnation
was observed.
    Emmett  et  al.   (1985)  demonstrated  by changes  1n  crossed  Immunoelectro-
phoresls patterns  that 3,3'-d1methylbenz1d1ne  binds  to serum proteins.   As
demonstrated  by autoradlography,  3t3'-d1methylbenz1d1ne  bound  to  a and  0


0857p                               -22-                             06/10/87

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"Mpoprotelns.   The  authors  suggested  that bound  3,3'-d1methylbenz1d1ne  may
be  transported  to tissues  by serum proteins.   Wise et  al.  (1984)  reported
that  dog  bladder  transitional epithelial  prostaglandln  H synthase activated
3,3'-d1methylbenz1d1ne  binding  to  protein,   tRNA  and  DNA.   Tsurata  et  al.
(1985)  reported  that  the  peroxIdase/H.O-  system  catalyzed  the  binding  of
3,3'-d1methylbenz1d1ne to DNA.
5.7.   SUMMARY
    The  cardnogenldty of  3,3'-d1methylbenz1d1ne  has  not  been  adequately
assessed by oral  and  Inhalation routes  of  administration.  However,  there Is
a wealth  of animal  data  showing  that  a  high level and  varied carcinogenic
responses  do  occur  In  tissues  exposed to 3,3'-d1methylbenz1d1ne.   Gr1swoId
et  al.  (1968)  observed an  Increased   Incidence  of mammary  tumors   In  rats.
treated by gavage with  a  total of  500  mg/rat  over  30 days and observed for 9
months  compared  with  controls.    IARC  (1972),  however,  considered  this
experiment to be  of  doubtful significance because of  the  small  sample  size
(20 rats).
    No tumors were  observed 1n hamsters  treated with  3,3'-d1methylbenz1d1ne
1n  the  diet  at  0.1  or   0.3%  for  the  Hfespan  (Safflotl  et  al.,  1967;
Sellakumar et al., 1969).   Ferber  (1977)  reported a study  In which  one  case
of bladder cancer was  observed  In  1/4  dogs 8 years  after being fed  3,3'-d1-
methylbenz1d1ne  at  200 mg/day  for 8-9 months.    3,3'-D1methylbenz1d1ne  has
been  tested  by  the  National  Toxicology  Program  (NTP,  1986).   Preliminary
results  of hlstopathology  Indicate  that 3,3'-d1methylbenz1d1ne  Induces  a
carcinogenic  effect   In F344  rats  when  the compound   1s  administered  In
drinking water (Mennear, 1987).
0857p                               -23-                             06/10/87

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    Numerous cardnogenlclty studies by a  less  relevant  route of administra-
tion  were  available  as well.   In  rats  given subcutaneous  doses  of  3,3'-d1-
methylbenz1d1ne, tumors were observed  In the Zymbal  gland,  preputlal  gland,
forestomach,  skin,   lung  (PUss and  Zabezhlnsky,  1970),  heart  (rhabdomyo-
sarcoma)  (PUss  and  Vol'fson  1973),  and external  auditory  canal (Spitz  et
al.,  1950).   In  rats  subcutaneously   Implanted  with   pellets  containing
3,3'-d1methylbenz1d1ne,  Zymbal  gland,   mammary  gland,  skin,   liver   and
hematopoletlc system tumors were observed (PUss and Zabezhlnsky, 1970).
    Increased  Incidences  of mammary  and lung  tumors were  observed In  the
offspring  of  mice Injected  subcutaneously during  gestation  (Golub  et  al.,
1974).  The possible carcinogenic  effect  of  3,3'-d1methylbenz1d1ne In  humans
has not been  assessed  adequately.   Urinary system cancer  1n  workers exposed
                                        •
to mixtures of  benzldlne,  3,3'-d1methylbenz1d1ne and 3,3'-d1methoxybenz1d1ne"
has been  reported  (MacAlplne,  1947; Kuratsune and Takemura,  1969);  however,
adequate  1nterpret1on  of   these  results  are  confounded  by  the presence  of
benzldlne, a known human bladder carcinogen.
    The mutagenldty  of 3,3'-d1methylbenz1d1ne  has   been  tested  1n  various
prokaryotlc and eukaryotlc  systems.   3,3'-D1methylbenz1d1ne gave  predomi-
nantly positive results In the  S.  typhlmuMum reverse mutation  test  with S-9
metabolic   activation  (Reid et  al.,  1984a;  Waalkens  et  al.,  1981;  Anderson
and Styles,  1978;  Kenelly et  al., 1984; Lazear  and Louie,  1977; PMval  et
al.,  1984;   Ferettl  et al.,  1977).  Positive  results were obtained 1n  ONA
repair  tests   In  Escher1ch1a  coll  (N1sh1oka  and  Ogasawara,   1978)  and  In
hepatocytes Isolated from  rats  and  hamsters.  3,3'-D1methylbenz1d1ne Induced
UDS 1n HeLa cells with metabolic activation  (Martin  et al.,  1978).  Positive
and  negative  results,  respectively,  were  obtained  1n  oral  and Injection
studies 1n  the  sex-linked  recessive lethal tests 1n  Drosophlla melanoqaster
0857p                               -24-                             04/10/87

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(Valencia  et  al.,  1985).  Positive  results  were obtained  In  a mlcronucleus
test  In rats  (Clhak,  1979),  In  a  testlcular  DNA  synthesis  test  1n  mice
(Seller,  1977)  and  In  a  cell  transformation  test  In   rat  embryo  cells
(Freeman et al., 1973).
    The  teratogenldty  of  3,3'-d1methylbenz1d1ne  has  not been  adequately
assessed by  a relevant  route  of  administration.  Wilson  (1955)  observed  no
malformations  1n  progeny  of   pregnant   rats   subcutaneously   Injected  with
3,3'-d1methylbenz1d1ne,  but did observe an ~1% Increase of resorptlons.   Ema
et al.  (1984)  did  not observe fetotoxlc  effects  1n  progeny of  rat dams  sub-
cutaneously  Injected  with 3,3'-d1methylbenz1d1ne.   Pertinent  data regarding
the reproductive  effects of 3,3'-d1methylbenz1d1ne  could  not  be  located  1n
the available literature as cited In the Appendix.
    The  chronic  and  subchronlc  toxlclty of  3,3'-d1methylbenz1d1ne  has  not
been studied.
0857p                               -25-                             10/01/86

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                             6.  AQUATIC TOXICITY

    Pertinent  data ~regarding  effects  of  3,3'-d1methylbenz1d1ne  on  aquatic
biota  could not  be   located  1n  the available  literature  as  cited  1n  the
Appendix.
0857p                               -26-                             10/01/86

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                     7.   EXISTING GUIDELINES AND STANDARDS
7.1.   HUMAN
    ACGIH  (1985-1986,  1986)  did  not   recommend   or  adopt  a  TLV-THA  for
3,3'-d1methylbenz1d1ne and  considered  this compound to  be  a  suspected human
carcinogen.   U.S.  EPA (1981)  decided  not  to  require additional  health  and
environmental  effects testing of  benzldlne,  o-to!1d1ne  and  o-d1an1s1d1ne
based  dyes.    NIOSH   (1978)  recommended  that  3,3'-d1methylbenz1d1ne  "be
handled as a  suspect  human carcinogen,"  and  that  "exposure to o-to!1d1ne be
kept as low as  possible  through  strict  adherence to a program of monitoring,
engineering controls  and  stringent  work practices."  Occupational  exposure
should  not   exceed   20  yg/m3   1n   air,   "determined   from  an  air  sample
collected  at  0.2 liters/minute  for  60 minutes."   Users of  laboratory test
tapes and  kits  containing  3,3'-d1methylbenz1d1ne were  excluded from monitor-
Ing and  surveillance  requirements of this  recommended  standard.   OSHA/NIOSH
(1980) published a Health Hazard Alert for 3,3'-d1methylbenz1d1ne-based dyes.
7.2.   AQUATIC
    Guidelines  and  standards for  the  protection of  aquatic  biota  from  the
effects  of 3,3'-d1methylbenz1d1ne  could  not  be   located  1n  the  available
literature as cited In the Appendix.
0857p                               -27-                             10/01/86

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                              8.   RISK  ASSESSMENT

    The  cardnoger>1c1ty  of  3,3'-d1methylbenz1d1ne has  not been  adequately
assessed  by  the  oral .and  Inhalation  routes  of  administration.   However,
there  Is  a wealth of animal  data  showing  that  a  high level and  varied  car-
cinogenic  responses  do occur  1n  tissues  exposed  to  3,3'-d1methylbenz1d1ne.
Grlswold  et  al.   (1968) observed  a 19% Incidence  of  mammary tumors  1n  rats
treated by gavage with a total of  500  mg/rat  over  30  days and  observed for  9
months  compared  with  4%   In  control   rats,  which  were  pooled  from  several
experiments.   IARC   (1972),  however,   considered   this  experiment  to  be of
doubtful significance because of  the small  sample  size (20 rats).
    No  tumors  were  observed  In hamsters treated with 3,3'-d1methylbenz1d1ne
1n  the  diet   at  0.1  or   0.3% for  the  Hfespan  (Saff1ot1  et  al.,  1967;'
Sellakumar et  al.,  1969).   Ferber  (1977)  reported a  study  In which  one  case
of bladder cancer was  observed In 1/4 dogs 8 years after  being  fed  3,3'-d1-
methylbenzldlne at  200 mg/day for  8-9 months.    3,3'-D1methylbenz1d1ne  has
been  tested  by  the National  Toxicology  Program  (NTP,  1986).   Preliminary
hlstopathology data  Indicate  that 3,3'-d1methylbenz1d1ne  Induces  a  carcino-
genic  effect   In  F344 rats  when  the  compound  1s  administered  In  drinking
water (Hennear, 1987).
    Numerous carc1nogen1c1ty  studies  by  subcutaneous  and  Injection  adminis-
tration are available as well.  In  rats given subcutaneous  doses  of  3,3'-d1-
methylbenzldlne,  tumors were  observed  1n  the Zymbal  gland,  preputlal  gland,
forestomach,  skin,  lung  (PUss  and  Zabezhlnsky,   1970),  heart  (rhabdomyo-
sarcoma)  (PUss and Vol'fson  1973),  and  external  auditory  canal  (SpHz et
al.,   1950).   In   rats  subcutaneously  Implanted   with   pellets   containing
3,3'-d1methylbenz1d1ne, Zymbal gland,  mammary gland,  skin,  liver and  hema-
topoletlc  system   tumo-s   were observed   (PUss   and Zabezhlnsky,   1970).

0857p                               -28-                              06/10/87

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Increased  Incidences  of mammary  and lung  tumors  were observed  In  the off-
spring  of  mice  Injected  subcutaneously  during  gestation  (GoTub   et  al.,
1974).  The  possible  carcinogenic effect  of 3,3'-d1methylbenz1d1ne In humans
has  not been assessed adequately.  Urinary system  cancer  1n workers  exposed
to mixtures  of  benzldlne,  3,3'-d1methylbenz1d1ne and 3,3'-d1methoxybenz1d1ne
has  been  reported (MacAlplne,  1947; Kuratsune and  Takemura, 1969);  however,
adequate  Interpretlon of  these  results are  confounded by  the  presence  of
benzldlne,  a known human  bladder carcinogen.   Given  the  available  positive
response  data  showing  that  3,3'-d1methylbenz1d1ne  causes a  carcinogenic
response  1n  various  animal tissues following tissue  exposure,  and knowledge
that  3,3'-d1methylbenz1d1ne  has  been Identified 1n  humans  exposed to benzl-
dlne  based  dyes,  3,3'-d1methylbenz1d1ne  1s given  an  EPA  Group  82  welght-
of-ev1dence  ranking.   Preliminary  NTP  results  of a  new bloassay of  3,3'-d1-
methylbenzldlne  In  drinking  water  are  supportive  of  this  as  well  as  a
recognition  that,  while  Information   for  3,3'-d1methylbenz1d1ne alone  Is
nonexistent,  the  Information  for  3,3'-d1methylbenz1d1ne  and  benzldlne  and
3,3'-d1methoxybenz1d1ne are clearly positive for humans.
    The mutagenldty  of 3,3'-d1methylbenz1d1ne  has  been  tested  In  various
prokaryotlc  and eukaryotlc  systems.   3,3'-01methylbenz1d1ne has  been  shown
to   produce  gene  mutations   1n   Salmonella  typhlmurlum   after  liver  S-9
metabolic activation  (Reid et al.,  1984a;  Waalkens  et al.,  1981;  Anderson
and  Styles,  1978;  Kenelly  et  al.,  1984;  Lazear and  Lowle,  1977;  Ferettl  et
al.,   1977)  and   1n   DrosophUa   melanogaster   after  feeding  adult  males
(Valencia et al.,  1985).   Positive  results  were  obtained  1n ONA repair tests
1n Escherlchla  coll  (Nlshloka  and Ogasawara, 1978),  1n hepatocytes  Isolated
from  rats and  hamsters, and 1n  HeLa cells  with rat  liver  metabolic  activa-
tion  (Martin et  al.,  1978).   Positive results  were  obtained In a  micro-
nucleus test  In rats (C1hak,  1979),  but  negative  results  were reported  for

0857p                               -29-                             06/10/87

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reciprocal  translocatlons  1n  DrosophUa  (Valencia  et  al.,   1985).   In  a
testlcular DNA  synthesis  test 1n  mice  positive results  were  found (Seller,
1977).  3,3'-D1methylbenz1d1ne was  reported  to be positive  1n  a  cell  trans-
formation test In rat embryo cells (Freeman et al., 1973).
    Therefore,  the  welght-of-evldence Indicates  that  3,3'-d1methylbenz1d1ne
Is  mutagenlc  and may  pose a  risk to somatic  cells.   Mutations  In  somatic
cells  may lead  to   the  onset of  cancer,  developmental  abnormalities,  and
possibly  other  diseases.   Further, 3,3'-d1methylbenz1d1ne  Induces  heritable
mutations 1n DrosophUa and affects testlcular  DNA synthesis  In mice.   These
findings  suggest  that  3,3'-d1methylbenz1d1ne  (or  an  active form)  may  reach
the mammalian  gonad and  produce  mutations  In  germ cells.   Germ  cell  muta-
tions may be  passed on to  future generations and  Increase  the Incidence  of
genetic  disease In  the  population.   The above  conclusions are  consistent
with  the  welght-of-evldence approach  described 1n  the U.S. EPA  guidelines
for mutagenlcHy risk assessment  (U.S. EPA, 1986c).
    The  teratogenlclty of  3,3'-d1methylbenz1d1ne  has  not  been  adequately
assessed by a  relevant route  of  administration.   Wilson  (1955) observed  no
malformations   1n progeny  of  pregnant  rats  subcutaneously   Injected  with
3,3'-d1methylbenz1d1ne, but did observe an ~7X Increase of  resorptlons.   Ema
et al.  (1984) did not  observe fetotoxlc effects 1n progeny  of  rat  dams  sub-
cutaneously  Injected with 3,3'-d1methylbenz1d1ne.   Pertinent data  regarding
the reproductive  effects  of 3,3'-d1methylbenz1d1ne could not   be  located  In
the available  literature as cited  In the Appendix.
    The chronic  toxlclty of 3,3'-d1methylbenz1d1ne  has  not been  studied.
    3,3'-01methylbenz1d1ne  Is  considered  to  be an animal carcinogen and  1s
suspected of  being  carcinogenic   to  humans  (IARC,  1972,  1979;  NIOSH,  1978;
OSHA/NIOSH,  1980; ACGIH,  1986) and  by  EPA  (with  this  assessment).  An  EPA
1986  (reportable quantity)  carc1nogen1c1ty  evaluation,  which  assigned  a
0857p                               -30-                             06/10/87

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weight of  evidence  of limited animal  data  (Group C), Is  superceded  by  this
Group  B2  ranking 1n  this risk  assessment.   NIOSH  (1978) recommended  that
3,3'-d1methylbenz1d1ne be  handled  as  a  suspect  human carcinogen  based  upon
positive  results  1n   mutagenldty   studies  and  development  of  tumors  In
rodents.   OSHA/NIOSH  (1980)  published a  Health Hazard  Alert  for  3,3'-d1-
methylbenzldlne  based dyes.   ACGIH  (1985-1986,  1986)  considered  3,3'-d1-
methylbenzldlne  a  suspected  human  carcinogen   and  noted  Its   structural
similarity to the known human bladder carcinogen,  benzldlne.
    Given  the  above  cardnogenldty classifications, 1t  1s  Inappropriate  to
derive an  RfO  (formerly  called ADI).  For cardnogenldty, however,  consid-
eration of  deriving  a  cancer potency  Is appropriate.   All  of the  studies
that  used  a relevant  route  of administration (oral)  are flawed  to  varying
degrees and thus the  quantitative risk assessment will necessarily have  some'
additional uncertainty.
    Grlswold et al.  (1968) observed an Increased  Incidence  of mammary tumors
(3/16, 19%) 1n 20 female rats  given  10 doses of  50  mg of  3,3'-d1methylbenz1-
dlne  by gastric  Intubation over 30  days,  followed  by a  9-month observation
period compared  with  pooled  controls  (5/132,  4%).    The  purity of the  com-
pound administered was not reported, only one sex was  tested  for a period  of
time  (30 days), which was  substantially less than the  Hfespan  of  the animal
(2  years),  size  of the  group tested  was  small   (20)  and was  compared  with
pooled  controls,  and  limited hlstopathologlcal   examination  was  performed.
The data  were  also not  statistically analyzed  by  the author.   IARC  (1972)
considered  this  study to  be  of  doubtful significance  because  of   the  small
sample size tested.   While the noted deficiencies exist,  this study has  been
selected  for  derivation  of  cancer  potency.   The  q * was  determined  from
this data  to be 9.2  (mg/kg/day)'1 as shown 1n Table  8-1.

0857p                               -31-                              06/11/87

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                                   TABLE  8-1
      Derivation of Potency Factor (F factor) for 3,3'-D1methylbenz1d1ne
Reference:
Exposure route:
Species:
Strain:
Sex:
Body weight:
Duration of treatment:
Duration of study:
Ufespan of animal:
Tumor site, type:
Nominal dose:
Average dally dose:
Equivalent human dose:
Tumor Incidence:
Potency (q-j*):
Potency (1/ED10): -
GHswold et al., 1968
gastric Intubation with sesame oil
rat
Sprague-Dawley
female
0.35 kg (assumed)
1 month (10 doses 3 days apart)
9 months
24 months (assumed)
mammary carcinomas and hyperplasla
Control
 0.00
 0.00
 0.00
 5/132
 9.2 mg/kg/day
 34.1
                                                        Animal
500.00 mg (total lifetime dose)
  5.29 mg/kg/day
  0.90 mg/kg/day (surface-area adj)
  3/16
Q857p
        -32-
                           06/11/87

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    Safflotl  et  al.  (1967)  and  Sellakumar et  al.  (1969) gave  hamsters  0.1
and 0.3% dietary 3,3'-d1methylbenz1d1ne  for  their  Hfespan and  observed  no
tumors.  Ferber  (1977)  observed  bladder cancer 1/4 dogs  8  years  after being
fed a  total  of 50 g 3,3'-d1methylbenz1d1ne  for 8-9 months.   This  study  was
not reported  1n sufficient  detail  to  support  a  risk  assessment.   Numerous
studies  1n  which  3,3-d1methylbenz1d1ne was administered  subcutaneously were
available; however, a  conventional  risk assessment  cannot be  based  on these
studies  because  of  the routes of  administration  and the related difficulty
of  estimating an effective  dose  comensurate with  oral or   Inhalation expo-
sure.   Urinary  system  cancer  1n  workers exposed to  mixtures of benzldlne,
3,3'-d1methylbenz1d1ne    and   3,3'-d1methoxybenz1d1ne   has   been   reported
(MaCalplne, 1947; Kuratsune  and Takemura,  1969);  however, adequate Interpre-
tation of  these  results   for  3,3'-d1methylbenz1d1ne are  confounded  by  the
presence  of   benzldlne,  a  known  human  bladder carcinogen.   NTP (1986)  Is
testing  3,3'-d1methylbenz1d1ne  for  cardnogenlcHy.  Preliminary  results  of
hlstopathology  Indicate  that  3,3'-d1methylbenz1d1ne  Induces  a  carcinogenic
effect  In  F344  rats  when  the compound  1s  administered  In  drinking water
(Mennear, 1987).
0857p                               -33-                             06/10/87

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                           9.   REPORTABLE  QUANTITIES
9.1.   REPORTABLE QUANTITY (RQ) RANKING BASED ON CHRONIC TOXICITY
    No  chronic  or- subchronlc  oral  or  Inhalation  studies  of 3,3'-d1methyl-
benzldlne were  available;  therefore, data  are  Insufficient  to  derive  an RQ
based on chronic toxldty (Table 9-1).
9.2.   WEIGHT OF EVIDENCE AND POTENCY FACTOR (F*1/ED1Q) FOR CARCINOGENICITY
    3,3'-01methylbenz1d1ne  1s  considered  to  be  an animal and/or  suspected
human  carcinogen  (NIOSH,  1978;  OSHA/NIOSH,  1980;  ACGIH, 1985-1986,  1986;
IARC, 1972,  1979)  and EPA  (In  this assessment); however,  most  oral  studies
were  sufficiently  flawed  and  precluded  their  use  In  quantitative  risk
assessment.  In  female rats given  10  doses of  50  mg  3,3'-d1methylbenz1d1ne
by gastric Intubation  over 30  days  followed by  a 9-month observation period,
Grlswold  et  al.  (1968)  observed  an Increased  Incidence  of  mammary  tumors
(3/16,  19X)  compared with  pooled controls (5/132,  4%).   The purity  of  the
compound administered was not  reported, only one sex was  tested  for a period
of  time (30 days),  which was  substantially  less  than  the  Hfespan  of  the
animal  (2  years),  size of the  group tested was small  (20) and  was compared
with  pooled  controls,  and  limited hlstopathologlcal   examination  was  per-
formed.  The data were also  not  statistically  analyzed.   IARC (1972)  consid-
ered  this  study  to be of  doubtful significance because of the  small  sample
tested.  Saff1ot1  et  al.  (1967)  and Sellakumar et  al.  (1969) gave hamsters
0.1 a'nd  0.3X dietary 3,3'-d1methylbenz1d1ne for  their Hfespan  and observed
no  tumors.   Ferber  (1977)  observed bladder  cancer 1n  one  of  four  dogs  8
years  fafter being  fed  a  total  of   50 g 3,3'-d1methylbenz1d1ne  for  8-9
months.  This study was  not  reported In  sufficient  detail  to support a risk
assessment.  Numerous  studies  In  which 3,3'-d1methylbenz1d1ne  was  adminis-
tered subcutaneously were available  (see  Section 5.1.);  however, they cannot
support a risk assessment because  of the  Irrelevant route  of  administration.

0857p                               -34-                             06/10/87

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                                   TABLE  9-1
                            3,3'-D1methylbenz1d1ne
           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
0857p                               -35-                             06/10/87

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Urinary system cancer  In  workers  exposed to mixtures  of  benzldlne,  3,3'-di-
methyl benzldlne  and  3,3'-d1methoxybenz1d1ne  has  been reported  (MacAlplne,
1947;  Kuratsune  and  Takemura, 1969);  however,  adequate  Interpretation  of
these  results  are confounded  by   the  presence  of  benzldlne,  a  known human
bladder  carcinogen.   NTP   (1986)   has   tested  3,3'-d1methylbenz1d1ne  for
carc1nogen1dty.   Preliminary  hlstopathology  results  Indicate  that  3,3'-d1-
methylbenzldlne Induces a carcinogenic effect  1n F344  rats  when the  compound
1s  administered  In drinking  water  (Hennear,  1987).   From Grlswold  et  al.
(1968) and this data a potency  factor  (F)  of  34, a potency group of  2 and an
EPA  Grouping of  B2  were  determined,  which  gives  3,3'-d1methylbenz1d1ne  a
MEDIUM hazard  ranking.   The documentation  supporting  this ranking  was  dis-
cussed 1n  Chapter 8.   Nevertheless,  since  IARC  (1979) and U.S.  EPA (1986a)
consider  the  animal  data to be sufficient and  the  human data to be Inade-
quate, 3,3'-d1methylbenz1d1ne   1s  most appropriately  classified  as  an  EPA
Group  82   chemical,  that  1s,   a  possible  human carcinogen.   When   the  NTP
current  study  on  3,3'-d1methylbenz1d1ne  becomes  available,  this  cancer
evidence  w1l* be  reevaluated and  1t  will be reclasslfled based on the level
of carcinogenic evidence.
0857p                               -36-                             06/11/87

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                                10.   REFERENCES

ACGIH  (American Conference  of  Governmental  Industrial  Hyg1en1sts).   1985-
1986.   TLVs:  Threshold. Limit  Values  for  Chemical  Substances  and  Physical
Agents  1n  the  Workroom  Environment  with  Intended  Changes  for  1985-1986.
Cincinnati, OH.

ACGIH  (American Conference  of  Governmental  Industrial  Hyglenlsts).   1986.
Documentation  of  the  Threshold Limit   Values,  5th  ed.   Cincinnati,  OH.
p. 577.

Anderson,  D.  and J.A.  Styles.   1978.  An  evaluation  of 6  short-term tests
for  detecting  organic  chemical carcinogens.   Appendix 2.  The  bacterial
mutation test.  Br.  0. Cancer.  37:  924-930.

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: 1609-1015.

Bowman, M.C., W.L. Oiler, C.R.  Nony,  K.L. Rowland and  S.M.  BUledean.   1982.
Metabolism  and  distribution  of two  l4C-benz1d1ne-congener-based  dyes  1n
rats  as determined  by  GC,   HPLC  and radloassays.   J.  Anal.  Toxlcol.   6:
164-174.

C1hak, R.   1979.  Evaluation  of benzldlne by the mlcronucleus  test.   Hutat.
Res.  67: 383-384.
0857p                               -37-                             06/10/87

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Oleteren,  H.M.   1966.  The  blotransformatlon  of o-to!1d1ne.   A qualitative
Investigation.  Arch. Environ. Health.  12(1):  30-32.

Ema,  M.,  H.  Kawasaki, Y. Ogawa,  T.  Sta1m1  and S. Kanoh.   1984.   Studies  on
the  pharmacological   bases   of  fetal  toxlclty  of  drugs.   VI.  Teratogenlc
effect of  trypan  blue and Its related compounds  1n rats.   Toxicology.   101:
161.

Emraett,  M.,   C.E.  Cern1gl1a  and  A.J.   Crowle.   1985.   Differential  serum
protein  binding  of  benz1d1ne-based  dyes and  benzldlne  congener  based  dyes
and their derivatives.  Arch. Toxlcol.  57(2):  130-135.

Ferber, K.H.  1977.   Carc1nogen1c1ty  of  orthotoUdlne 1n  the  urinary bladder
of  the dog.   Unpublished report  submitted to  NIOSH  by  Ferber  KH,  Allied
Chemical  Division, Buffalo Dye Plant, Specialty  Chemicals  Division,  Buffalo.
p. 11.  (Cited In NIOSH,  1978)

Ferber,  K.H.   1978.   Benzldlne  and related  b1phenyld1am1nes.   In.:  K1rk-
Othmer Encyclopedia  of Chemical  Technology,  Vol.  3,  3rd ed.,  M.  Grayson and
D. Eckroth, Ed.  John Wiley and Sons, Inc.,  New York.  p.  775.

Ferrettl,  J.J.,  W.  Lu and  M. Liu.  1977.  Mutagenldty  of benzldlne  and
related compounds  employed  In  the  detection  of hemoglobin.   Am.  J.  CUn.
Pathol.  67(6):  526-527.
0857p                               -38-                             06/10/87

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Freeman,  A.E.,  E.K.  Helsburger,  J.H.  Welsburger,  R.G. Wolford,  J.M.  Maryak
and  R.J.  Huebner.   1973.  Transformation of  cell  cultures as  an  Indication
of  the  carcinogenic  potential  of chemicals.   J.  Natl. Cancer  Inst.   51(3):
799-808.

Golub, N.I., T.S. Kolesnlchenko and L.M. Shabad.   1974.   Oncogenlc  action  of
some  nitrogen  compounds on  the  progeny  of experimental  mice.  Bull.  Exp.
B1ol. Med. (USSR).   78: 1402-1404.

GMswold, D.P., Jr., A.E. Casey,  E.K. Welsburger and  J.H.  Welsburger.   1968.
The  carclnogenlcHy  of multiple  IntragastMc  doses  of aromatic and  hetero-
cycllc  nltro  or  amlno  derivatives  1n^ young female  Sprague-Oawley  rats.
Cancer Res.  28(5):  924-933.

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

Holland,  V.R.,  B.C.  Saunders,   F.L.  Rose and  A.L.  Walpole.   1974.   A  safer
substitute  for benzldlne  In  the  detection   of   blood.   Tetrahedron.   30:
3299-3302.

IARC  (International  Agency for  Research on Cancer).   1972.   IARC Monographs
on  the  Evaluation  of  the  Carcinogenic  Risk  of Chemicals  to  Man.   3,3-01-
methylbenzldlne (o-to!1d1ne).   WHO,  IARC, Lyons,  France.   Vol. 1,  p.  87-91.

IARC  (International  Agency  for Research on  Cancer).   1979.   IARC  Monograph
on the Evaluation of  the Carcinogenic  Risk of Chemicals  to Man.  WHO,  IARC,
Lyons, France.   IARC Suppl. 1.

0857p                               -39-                             06/10/87

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Karstadt,  M.,  R.  Bobal and  I.J.  Sellkoff.  1981.   A  survey of availability
of  epldemlologlc  data  on  humans  exposed to  animal   carcinogens.   Banbury
Report.  9: 223-246.

Kennelly,  J.C., C.A. Stanton and  C.N.  Martin.   1984.  The effect of acetylco
a  supplementation  on  the  mutagenldty  of  benzldlnes  In  the ames  assay.
Mutat. Res.  137:  39-45.

Kornbrust,  D.O.  and T.R.  Barfknecht.   1984.    Comparison  of 7  azo  dyes  and
their  azo  reduction  products  1n  the rat  and  hamster  hepatocyte  primary
culture/DNA repair assays.  Mutat. Res.  136(3): 255-266.

Kornbrust,  D.J.  and  T.R. Barfknecht.   1985.    Comparison  of  azo dyes  and
their  reduction   products  genotoxldty  1n rat and  hamster hepatocyte  DNA
repair assay.  Environ. Mutagen.  7(suppl. 3):  70.

Kuratsune,  M.  and  N.  Takemura.   1969.   Occupational  cancer.   .In,:  Occupa-
tional Health  In  Japan,  H.  K1ta,  Ed.  Tokyo,  Organizing Committee  of  the
Sixteenth  International  Congress  on Occupational  Health,   p.  62-68.   (Cited
1n NIOSH, 1978)

Lapp,  T.W., T.L.  Ferguson,   H.  Gadberry,  F.   Haffmelster  and F.  Hopkins.
1981.  Materials  balance  for   dyes  and  pigments  from  benzldlne  and  three
benzldlne  derivatives.   Office of  Toxic  Substances,  U.S.  EPA,  Washington,
DC.  EPA 560/2-81-001.   NTIS  PB81  224289.
0857p                               -40-                             06/10/87

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Lazear,  E.J.   and  S.C.  Louie.   1977.   Mutagenlclty  of  some congeners  of
benzldlne  1n  the Salmonella  typhlmuMum  assay system.   Cancer  Lett.   4(1):
21-26.

Lowry,  L.K.,  W.P.  Tolos,  M.F. Boenlger,  C.R.  Nony and  M.C.  Bowman.   1980.
Chemical  monitoring  of urine  from  workers  potentially  exposed  to benzldlne
— Drives azo dyes.   Toxlcol. Lett.   7(1):  29-36.

Lurle,  A.P.    1964.   Tol1d1nes.  In.:  K1rk-0thmer  Encyclopedia  of  Chemical
Technology, Vol. 3, 2nd ed.,  A.  Standen, Ed.   John Wiley and Sons, Inc.,  New
York.  p. 414.

Lyman,  W.3.,  W.F.  Reehl  and O.H.  Rosenblatt.  1982.   Handbook of  Chemical
Property  Estimation Methods.   McGraw-Hill Book  Co.,  New York.   p.  2-14,  4-9,
5-5, 7-4.

MacAlplne, J.B.  1947.  Papllloma of  the  renal pelvis  1n dye  workers  —  Two
cases, one of which shows  bilateral  growths.   Br.  J. Surg.  35: 137-140.

Martin, C.N., A.C. McOermld  and  R.  Garner.   1978.   Testing of  known carcino-
gens and  noncarclnogens for  their ability  to  Induce unscheduled DNA synthe-
sis In hela cells.   Cancer Res.  38: 2621-2627.

Melgs,  3.W.,  L.3.  Sclarlnl and  W.A.  Van  Sandt.   1954.   Skin  penetration by
dlamlnes of the benzldlne  group.  Arch.  Industr. Hyg.  9: 122.
0857p                               -41-                             06/10/87

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Mennear, Or.   1987.   National Toxicology Program,  Washington,  DC.  Personal
communication with Dr.  C.  Hlremath,  Carcinogen Assessment Group, Washington,
DC.  May.

Neely,  W.B.  and G.E.  Blau.   1985.  .In.:  Environmental  Exposure  from Chemi-
cals. Vol.  1.  CRC Press Inc., Boca Raton, FL.  p. 30-31.

NIOSH   (National  Institute  for  Occupational  Safety  and  Health).   1978.
Criteria for  a Recommended  Standard...Occupational Exposure  to o-Tol1d1ne.
U.S.  DHEW,  PHS, CDC,  Rockvllle,  HD.   Publ.   No.  78-79.   NTIS  PB81-227084.
88 p.

NIOSH   (National  Institute  for  Occupational  Safety  and  Health).   1980.
Special  Occupational  Hazard  Review for  Benzldlne  Based  Dyes.    U.S.  DHEW,
PHS, CDC, Rockvllle,  MD.  Publ.  No. 80-109.

N1sh1oka,  H.  and  H.  Ogasauara.   1978.  Mutagenlclty  testing  for  dlphenyl
derivatives 1n bacterial systems.  Mutat.  Res.  54: 248-249.

NTP (National Toxicology Program).  1986.   Management Status  Report.

OSHA/NIOSH  (Occupational Safety  and  Health  Administration/National Institute
for Occupational Safety and Health).  1980.   Health Hazard Alert: Benzldlne,
o-To!1d1ne  and o-D1an1s1d1ne-Based Dyes.  DHHS (NIOSH) Publ.  No.  81-106.

Parrls,  G.E.   1980.   Covalent  binding  of  aromatic  amines  to  humates.   1.
Reactions  with  carbonyls  and   qulnones.   Environ.  Sc1.  Technol.   14(9):
1099-1106.

0857p                               -42-                             06/10/87

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PUss, G.B.  1963.  On  some  regular  relationships between cardnogenldty of
ara1nod1phenyl  derivatives  and  the  structure  of  substance.   Acta  Un. Int.
Cancer.  19: 499. •

PUss,  G.B.   1965.    Concerning carclnogenous  properties  of  ortho-toUdlne
and d1an1s1d1ne.  Gig. Tr.  Prof. Zabol.   9:  18.   (Cited  In IARC, 1972)

PUss, G.B. and  N.I.  VoVfson.  1973.  Cardla rhabdomyosarcoma Inducted 1n a
rat  under  the  action  of   o-to11d1ne.   Vop.  Onkol.    19(3):  98-99.   (CA
79:1170y)

PUss,  G.B.  and M.A.   Zabezhlnsky.    1970.    Properties   of  orthotolldlne
(3,3'-d1methylbenz1d1ne).   J. Natl.  Cancer  Inst.  45: 283.

Powell,  R.,  M.  Murray,  C.  Chen  and  A.  Lee.  1979.  Survey of the manufac-
ture,  Import  and uses  for  benzldlne  related  substances   and  related sub-
stances  and  related  dyes  and  pigments.   Office  of Toxic  Substances, U.S.
EPA, Washington, DC.  EPA-560/13-79-005.

Prlval,  N.J.,   S.J.   Bell,  V.D.  Mitchell,   M.D.  Pelperl  and  V.L.  Vaughan.
1984.  Mutagen1c1ty  of  benzldlne and  benzldlne-congener dyes  and  selected
monoazo dyes In a modified  Salmonella assay.   Mutat. Res.  136(1): 33-47.

Reid, T.M., C.Y.  Wang,  C.M.  King and  K.C.  Morton.   1984a.   MutagenlcHy  of
some  benzldlne  congeners    and  their  N-acetylated  and   N,N'-d1acetylated
derivatives  1n  different    strains  of  Salmonella  typhlmurlum.   Environ.
Mutagen.   6(2):  145-151.


0857p                               -43-                             06/10/87

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Reid,  T.M.,  K.C.  Morton, C.Y.  Wang  and C.M.  King.   19845.   Mutagenlclty of
azo  dyes  following  metabolism  by   different reductlve/oxldatlve  systems.
Environ. Mutagen. "6: 705-717.

Sadtler.   n.d.   Sadtler  Standard  Spectra.    Sadtler  Research  Laboratory,
Philadelphia, PA.

Saff1ott1, U., F. Cefls,  R.  Montesano and  A.R. Sellakumar.   1967.  Induction
of bladder  cancer  1n hamsters  fed aromatic amines.  ITK Bladder Cancer.   A
Symposium,  W.  Delchmann  and K.F. Lampe,  Ed.   Aesculapius,  Birmingham,  AL.
p. 129.

Schmltz,  G. and  H.  Rooze.    1981.   Reaction  mechanisms  for  chlorite  and
chlorine dioxide.  1. Sto1ch1ometry  of  chlorite reaction  and  kinetics  1n the
presence of ortho-toluldlne.   Can. J. Chem.  59(8): 1177-1187.

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

Sellakumar,  A.R.,  R.  Montesano  and  U. Saff1ott1.   1969.    Aromatic  amines
cardnogenldty In hamsters.   Proc. Am. Assoc.  Cancer Res.  10:  78.

Sololmskaya, E.A.   1970.   Activity of  some  enzymes  during the poisoning  of
animals  with  carcinogenic   aminodlphenyl-compounds.   Vopr.  Onkol.   16(4):
94-98.   (CA 12:2255h)
0857p                               -44-                             06/10/87

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Spitz, S., W.H.  Magulgan  and K.DobMner.  1950.  The  carcinogenic  action of
benzldlne.  Cancer.  3: 789-804.

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

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

Tsuruta,   Y.,   P.O.   Josephy,   A.D.  Rahlmtula  and   P.J.   O'Brien.    1985.
Peroxldase-catalyzed  benzldlne  binding   to   DNA  and  other  macromolecules.
Chem.-81ol.  Interact.  54(2): 143-158.

U.S.  EPA.   1977.   Computer print-out  of non-confidential  production  data
from TSCA Inventory.  OPTS, CID, U.S. EPA, Washington,  DC.

U.S.  EPA.    1979.   Water-Related  Environmental   Fate  of   129   Priority
Pollutants.  Vol.   II.   Office  of  Water   Planning  and  Standards,  Office  of
Water and Waste Management, U.S. EPA, Washington,  DC.  EPA  440/4-79-029b.

U.S.  EPA.   1980..  Preliminary  Risk Assessment:  Phase I.   Benzldlne,  Us
congeners and  their  derivative  dyes and  pigments.  Office of  Pesticides  and
Toxic Substances, Washington, DC.  EPA 560/11-80-019.
0857p                               -45-                             06/10/87

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U.S.  EPA.   1981.  Notice:  EPA 1n  Response  to ITC  Recommendations,  decides
not  to require  additional  testing  of  benzldlne, o-to11d1ne  and  o-d1an1s1-
dlne-based dye  for health and  environmental  effects.   Federal  Register.  46:
55004.

U.S.  EPA.   1986a.   Technical  Support  Document  and  Summary  Table for  the
Ranking  of  Hazardous  Chemicals  Based on  Cardnogenldty.   Prepared by  the
Office of  Health and  Environmental  Assessment, Carcinogen  Assessment  Group,
Washington, DC for the Office of Solid Haste, Washington, DC.

U.S.  EPA.    1986b.   Graphical  Exposure  Modeling  System  (GEMS).   Fate  of
Atmospheric  Pollutants  (FAP).    Office   of  Toxic   Substances,   U.S.   EPA,
Washington, DC.

U.S.  EPA.   1986c.   Guidelines  for MutagenlcHy  Risk  Assessment.   Federal
Register.  51(185): 34006-34012.

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

USITC  (U.S.  International   Trade  Commission).   1985.    Synthetic  Organic
Chemicals  United  States  Production  and  Sales,   1984.   USITC  Publ.  1745,
Washington, DC.

Valencia, R.,  J.M.  Mason,  R.C. Woodruff  and S.  Z1mmer1ng.  1985.   Chemical
mutagenesls testing In Drosophlla.   III. Results  of 48 coded compounds  test-
ed for the  National Toxicology  Program.   Environ.  Mutagen.  7(3):  325-348.


0857p                               -46-                             06/22/87

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Waalkens, D.H., H.F.P. Joosten, T.O.  Via  and  A.  Hoekstra.  1981.  Mutagenlc-
1ty   studies   with   o-to!1d1ne   and  4,4'-tetramethyld1am1nod1phenylmethane.
Mutat. Res.  89(3): 197-202.

Wilson,  J.G.   1955.   Teratogenlc  activity  of  several  azo dyes  chemically
related to trypan blue.  Anat. Rec.  123:  313-334.

Wlndolz,  M.,  Ed.   1983.   The Merck  Index,  10th ed.   Merck  and  Co.,  Inc.,
Rahway, N3.  p. 1362.

Wise,  R.W.,  T.V.  Zenger,  F.F.  Kadlubar  and   B.B.  Davis.  1984.   Metabolic
activation of carcinogenic aromatic amines by  dog bladder and  kidney prosta-
glandln H synthase.  Cancer Res.  44(5): 1893-1897.
0857p                               -47-                             06/10/87

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                                   APPENDIX

                              LITERATURE  SEARCHED



    This  profile  1s  based  on  data  Identified  by computerized  literature

searches of the following:


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


These  searches  were conducted  1n  April, 1986.   In addition,  hand  searches

were  made  of   Chemical  Abstracts  (Collective  Indices  6  and  7),  and  the

following secondary sources were reviewed:


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

    ACGIH  (American  Conference of Governmental  Industrial  Hyglenlsts).
    1985-1986.    TLVs:  Threshold  L1mU  Values  for  Chemical  Substances
    and  Physical  Agents  1n  the  Workroom   Environment  with  Intended
    Changes for 1985-1986.  Cincinnati,  OH.   114 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  WHey  and
    Sons, NY.   p. 2879-3816.
0857p                               -48-                             06/10/87

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

    Grayson, H.  and D.  Eckroth,  Ed.  1978-1983.   Klrk-Othmer  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.

    ITII  (International  Technical  Information  Institute).   1982.   Toxic
    and  Hazardous  Industrial  Chemicals Safety  Manual   for  Handling  and
    Disposal with Toxldty and Hazard Data.   ITII, Tokyo,  Japan.   700 p.

    Jaber,  H.M.,  W.R.  Mabey, S.T.  Liu,  T.W.  Chow and   H.L.  Johnson.
    1984.  Data aqulsltlon  for environmental  transport  and fate  screen-
    Ing  for  compounds  of  Interest  In the  Office of Solid  Waste.   EPA
    600/6-84-010.  NTIS PB84-243906.  SRI  International, Menlo Park,  CA.
                                        •

    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, N.I.  1979.  Dangerous  Properties  of  Industrial  Materials,  5th
    ed.  Van Nostrand Relnhold Co., NY.

    SRI  (Stanford   Research  Institute).   1984.   Directory of  Chemical
    Producers.   Menlo Park,  CA.

    U.S.  EPA.   1985.   Status  Report  on  Rebuttable  Presumption  Against
    Registration (RPAR)  or  Special Review  Process.   Registration  Stan-
    dards 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).    1983.    Synthetic
    Organic  Chemicals.   U.S.  Production  and  Sales,  1982, USITC  Publ.
    1422, Washington,  DC.

    Verschueren,  K.   1983.   Handbook of  Environmental  Data on  Organic
    Chemicals.  2nd  ed.   Van  Nostrand Relnhold  Co., NY.
0857p                               -49-                             06/10/87

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U.S. Environmental  Protection Agency.
Region V, Library                -
230  South Dearborn Street  ^
Chicago, Illinois  60604

-------
    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.


    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. Mnley.   1980.  Handbook of  Acute Toxldty
    of  Chemicals  to  Fish 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.
0857p                               -50-                             06/10/87

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